INDEX

Note: Page numbers followed by “f ” and “t” indicate figures and tables respectively.

A1-Acylglycerol-3-phosphate acyltransferase

(AGPAT), 174–175AA. See Arachidonic acidAA CYP4-produced hydroxyeicosatetrae-

noic acid (20-HETE), 200cardiomyocyte apoptosis, 245–246CYP4A and CYP4F, 204–205eicosanoids, 244–245endothelial dysfunction, 200–201repression of, 225

ABC. See ATP-binding cassette transporterABCA1. See ATP-binding cassetteACBPs. See Acyl-CoA binding proteinsACC. See Acetyl-CoA carboxylaseACC tool. See Asthma Control Composite

toolAcetyl-CoA carboxylase (ACC), 28,

169–170, 192–193ACOX. See Acyl-CoA oxidaseACQ. See Asthma control questionnaireACS. See Acyl-CoA synthetaseACSL. See Long-chain acyl-CoA synthetaseACTH. See Adrenocorticotropic hormoneActivator proteins (APs), 220, 272–273Acute lymphoblastic leukemia (ALL),

143–144Acyl-CoA binding proteins (ACBPs),

162–163, 169–170. See also Fatty acid binding proteins (FABPs)

eicosanoidsand HNF4α, 172transportation by, 171

FA transporters, 172–173fatty acid transport to nucleus, 172function and subcellular location, 160f–161fLCFA FA oxidation, 172nuclear localization region, 171proteins, 173role in MetS and NAFLD, 170

Acyl-CoA oxidase (ACOX), 171, 202f–203f

A

AAAA

AA

AAAA

AAAA

AA

A

A

AAA

313

cyl-CoA synthetase (ACS), 158–159FAs, ACS channeling in, 173–174

D. See Atopic dermatitisdalimumab, 58f, 59t, 63–64daptive immune priming, 82DCC. See Antibody-dependent

cytotoxicityDH4. See Alcohol dehydrogenasedipocyte fatty acid binding proteins

(A-FABPs), 167diponutrin. See PNPLA3 enzymesdipose tissue, 234–235dipose tissue macrophage (ATM), 191dipose triglyceride lipase (ATGL),

176–177, 209, 227–228dipose-specific PLA (AdPLA2), 187–188dPLA2. See Adipose-specific PLADR. See Adverse drug reactiondrenocorticotropic hormone (ACTH),

223–224dverse drug reaction (ADR), 224–225-FABPs. See Adipocyte fatty acid binding

proteinsGP. See Aminoalkyl glucosaminide

4-phosphateGPAT. See 1-acylglycerol-3-phosphate

acyltransferaseHR. See Airway hyperreactivityirway hyperreactivity (AHR), 3–4irway inflammationin asthma

corticosteroids effects on, 8inflammatory cytokines, 5–6type 2 alarmins, 6–7, 7ftype 2 inflammation, mediators of, 7f

biomarkers, 12–13blood eosinophil counts, 13–14eosinophil-specific oxidative enzymes, 13FeNO and iNOS, 13ICS dose, 14–15soluble blood biomarkers, 14

Index

314

AKR. See Aldo-keto reductaseALA. See α-linoleic acidAlcohol dehydrogenase (ADH4), 206ALDH32a, 206Aldo-keto reductase (AKR), 192ALL. See Acute lymphoblastic leukemiaAllergen challenge model, 23–24Allergic airway disease

lung expression of TSLP, 139role for TSLP in, 136–137

in challenge stage, 138in sensitization/priming stage, 138

Allergic rhinitis (AR), 136Alox5 gene, 194–195α-linoleic acid (ALA), 161ALT. See Serum alanine aminotransferaseAltrakincept, 15Amino-terminal regulatory domain, 271–272Aminoalkyl glucosaminide 4-phosphate

(AGP), 106chemical and metabolic stability, 108–109crystal structure, 109intravenous administration, 108modifications, 106–108SACs, 108structures, 106, 107f

AMP protein kinase (AMPK), 168AMPK. See AMP protein kinaseAnergic T cells, 287–288Anti-TNF inhibitors, 63Antibody-dependent cytotoxicity

(ADCC), 61Antigen-presenting cells (APCs), 82,

283–284Antiinflammatory LTA4 (Lipoxin), 162APs. See Activator proteinsAPCs. See Antigen-presenting cellsAPOE. See apoE lipoproteinapoE lipoprotein (APOE), 190A proliferation-inducing ligand

(APRIL), 132AR. See Allergic rhinitisArachidonic acid (AA), 158–159, 241–242Asthma, 4

airway inflammationcorticosteroids effects on, 8inflammatory cytokines, 5–6type 2 alarmins, 6–7

biomarkers, 11PD biomarkers, 12predictive biomarkers, 11–12prognostic biomarkers, 12surrogate biomarkers, 12

heterogeneityAHR and type 2 inflammation

disconnection, 10fgranulocytic infiltration, 9–11type 2 inflammation, 8–9

severity, 4–5Asthma Control Composite tool (ACC

tool), 28Asthma control questionnaire (ACQ), 32ATGL. See Adipose triglyceride lipaseATM. See Adipose tissue macrophageAtopic dermatitis (AD), 134Atopic march, 136ATP-binding cassette (ABCA1), 167ATP-binding cassette transporter (ABC),

206–207efflux transporters, 206–207transporters, 207

Autoimmune diseases. See also Cardiometabolic diseases

immune tolerance, 145overexpression, 144RA and MS, 144–145SNPs, 145

BB lymphocytes, 133. See also T LymphocytesB-cell lymphoma-10 (Bcl10), 274–275Bactericidal/permeability-increasing

protein (BPI), 84Bacteroides thetaiotaomicron, 93–94BAD. See Bcl2-associated death promoterBAL. See Bronchoalveolar lavageBAT. See Brown adipose tissueBcl10. See B-cell lymphoma-10Bcl2-associated death promoter (BAD),

275–276Benralizumab, 17–18, 32Biomarker-guided clinical trial design, 29

biologic asthma therapies, 30ttargeting IL9 and TNFα, 35TNFα blocking agent etanercept,

35–36

Index 315

therapies targetingACQ, 32bronchial allergen challenge study,

33–34early- and late-phase reaction, 29–31IgE, 29–31IL13-blocking therapies, 31IL4, IL13, and receptors, 32–35IL5 and receptor, 32late-phase allergen response, 34–35omalizumab, 29–31phase 2a allergen challenge study,

31–32BMI. See Body mass indexBMT. See Bone marrow transplantationBody mass index (BMI), 177Bone marrow transplantation (BMT),

allogenic, 281–282Bovine serum albumin (BSA), 98BPI. See Bactericidal/permeability-increas-

ing proteinBronchial asthma, 3–4Bronchial thermoplasty (BT), 4–5Bronchoalveolar lavage (BAL), 8–9,

136–137Brown adipose tissue (BAT), 180–181BSA. See Bovine serum albuminBT. See Bronchial thermoplasty

Cc-Jun N-terminal kinase (JNK), 88,

170–171, 275c-Kit protooncogene, 292Calcineurin (CN), 269–270Cancer, 142–143

solid tumors, 143–144TH2 cytokines promote disease, 143TSLP and TSLP signaling pathways, 144

CAR. See Constitutive androstane receptorCarbohydrate-responsive element binding

proteins (ChREBPs), 173–174Carboxy-terminal catalytic domain,

271–272CARD. See Caspase recruitment domainCardiolipin (CL), 184Cardiometabolic diseases

in eicosanoidsω-hydroxylase CYP4 pathway, 244–245

CVD, 244lipid intermediary metabolism, 245metabolic conditions, 242mitochondrial function, 245–246NSAIDs, 243prostanglandin synthases, 243–244

Cardiovascular disease (CVD), 161Carnitine palmitoyltransferase (CPT), 168Caspase recruitment domain (CARD),

274–275Caspase-1, 112CBC. See Complete blood countCC chemokine ligand (CCL), 14CCL. See CC chemokine ligandCD. See Crohn’s diseaseCD14, 84–85

amino glycolipids, 86benzylammonium lipids, 86S-LPS and R-LPS, 85TLR4 and MD-2, 85TLR4/MD-2/LPS complexes, 86TRIF-dependent signaling pathway, 85

CEL. See Chick embryo lethalityCentral supramolecular activation cluster

(cSMAC), 283–284Certolizumab, 58–59, 59tChemoattractant receptor homolog

(CRTH2), 214–216Chick embryo lethality (CEL), 97–98ChIP. See Chromatin immunoprecipitationChREBPs. See Carbohydrate-responsive

element binding proteinsChromatin immunoprecipitation (ChIP),

276Chronic obstructive pulmonary disease

(COPD), 136–137CHS. See Contact hypersensitivityCL. See CardiolipinClassical independent iPLA2IVA, 184–185Classical PKC. See Conventional PKC

(cPKC)CLS. See Crownlike structuresCN. See CalcineurinCoA. See Coenzyme ACoenzyme A (CoA), 158–159Complete blood count (CBC), 13–14ConA. See Concanavalin AConcanavalin A (ConA), 282–283

Index316

Constitutive androstane receptor (CAR), 219–220

Contact hypersensitivity (CHS), 135–136Conventional PKC (cPKC), 270–271COPD. See Chronic obstructive pulmonary

diseaseCore oligosaccharide, 90COX1. See Cyclooxygenase1cPKC. See Conventional PKCCPT. See Carnitine palmitoyltransferaseCRLF2. See Cytokine receptor-like factor

2Crohn’s disease (CD), 64, 140–141Crownlike structures (CLS), 236CRTH2. See Chemoattractant receptor

homologcSMAC. See Central supramolecular

activation clusterCTL. See Cytotoxic T lymphocyteCVD. See Cardiovascular diseaseCyb5A. See Cytochrome b5Cyb5R3. See Cytochrome b5 reductaseCyclooxygenase1 (COX1), 189–190

differential regulation, 189–190prostacyclin synthase colocalization, 191role in prostanoid production, 190

Cyclooxygenase2 (COX2), 167CYP. See Cytochrome P450Cysteine LT receptors, 216–217Cytochrome b5 (Cyb5A), 179–180Cytochrome b5 reductase (Cyb5R3),

179–180Cytochrome P450 (CYP), 194Cytokine receptor-like factor 2 (CRLF2),

143–144Cytokines, 52Cytosolic cPLA2IVA-null mice, 184Cytotoxic T lymphocyte (CTL), 275–276

DDAG. See DiacylglycerolDC. See Dendritic cellDendritic cell (DC), 130. See also TSLP-

responsive cellIEC, 132mDCs, 132

Detoxified lipid A analogs, 104

Dextran sulfate sodium (DSS), 141–142DHA. See Docosahexaenoic acidDHET. See Dihydroxyeicosatrienoic acidDiacylglycerol (DAG), 158–159, 175,

270–271Diet-induced obesity (DIO), 170–171Dihydroxyeicosatrienoic acid (DHET), 199DIO. See Diet-induced obesityDirect target binding assays, 20Distal supramolecular activation cluster

(dSMAC), 283–284Docosahexaenoic acid (DHA), 158–159,

180–181Dosing

altrakincept, 15IV or SC route, 15–16lebrikizumab, 16–17mepolizumab, 16–17MOA, 16–17

Double-stranded RNA (dsRNA), 139Drug development, 2–3

asthma pathophysiology links, 3fultimate objective, 2

dSMAC. See Distal supramolecular activation cluster

dsRNA. See Double-stranded RNADSS. See Dextran sulfate sodium

EE-FABPs. See Epidermal fatty acid binding

proteinsE. coli. See Escherichia coliE. coli lipid A analogs, 97–98

BSA, 98IL-1 α/β induction, 98inflammatory or endotoxic activity, 98SRBC, 98

EAE. See Experimental autoimmune encephalomyelitis

EAR. See Early-phase allergic responseEarly-phase allergic response (EAR), 29–31EC sensitization. See Epicutaneous

sensitizationEEQ. See EPA CYP2-produced epoxyeico-

satetraenoic acidEET. See Epoxyeicosatrienoic acidEffector T cell (Teff), 285

Index 317

EHHADH. See Enoyl-CoA hydratase 3-hydroxyacyl-CoA dehydrogenase

EIB model. See Exercise-induced bronchoconstriction model

Eicosanoid regulationeicosanoid G-protein-coupled receptors

BLT1 and BLT2, 216–217cysLT1 and cysLT2, 217EP1 and EP3 receptors, 214–216FFA receptors, 218LPLAT, 217–218LT and LX, 217LT receptors, 216–217prostanoid receptors, 214–216

fatty acid receptors, 213–214through GPCR, 209HNR family, 219LD formation, 213lipid mediators act, 213LRH-1, 222macrophages and dendritic cells, 223mechanism of regulation, 210t–212tmetabolic sensors, 219–220NAFLD, 218–219NR4A2/NURRI, 222–223NR4H4, 222PPARα, 220PPARβ, 220–221PPARγ, 221treatment of metabolic diseases, 221–222

Eicosanoid synthesis control, lipid metabolism in

ACS channeling, 173–174fatty acid transporters, 162–163

ACBP, 169–170ACBP and FABP, 171–173cellular uptake of FFAs, 170–171FABP, 166–169FATP, 163–166

phospholipase A2 roleAA incorporation into membrane, 181cPLA2, 182cytosolic cPLA2IVA-null mice, 184eicosanoid and metabolism, 188FFAs and LPC, 183HSPG-dependent and -independent

pathways, 182

E

human Ca2+-independent iPLA2, 184independent iPLA2IVA, 184–186iPLA2, 182intracellular iPLA2, 183–184lysosome PLA2 family, 187–188in MetS, 182PAF-AH family members, 187PLA2 functions, 181–182PNPLA2 and PNPLA3 enzymes,

186–187sPLA2, 182sPLA2 and atherosclerosis, 182–183

PUFA elongation, 180–181triacylglycerol synthesis

DAG and DGAT1, 175fatty acid transport and channeling,

174free AA cell pool, 175–176GPAT isoforms, 174insulin resistance, 177LPA and AGPAT, 174–175PAP/LP, 175TAG and PL metabolic pathways,

176–177unsaturated fatty acid desaturationΔ6-desaturase, 179–180linoleic and LA, 177–179metabolism of linoleic acid to,

178f–179ficosanoids, 158–159, 226in adipocyte metabolism

adipose tissue mass remodeling, 239–240

12/15-LOX pathway, 240in diabetes and insulin resistance

AA, 241–242pancreas, 240–241sEH-null mice, 242

function roles, 161links between sepsis and MetS

ADR and IADR, 224–225CYP gene expression, 225PGE2 and 11-HETE, 224sepsis or septicemia, 223–224

LX and inflammatory cascade, 162MetS, 161–162in NAFLD and obesity

Index318

Eicosanoids (Continued )ACSL5 expression, 228CYP4A genes and protein, 230–231drug metabolism, 232eicosanoid-metabolizing enzyme,

226–227, 233–234hepatic steatosis, 226immunological aspects, 233intrahepatic lipids and LD, 227–228SCD1 and ACC1 control, 229TAG synthesis, 229–230

purpose, 162in sepsis and drug metabolism, 223–224synthesis, 209transport and transcellular metabolism

human ABC transporters, 207MRP1/ABCC1, 207–208NAFLD, 208–209paracrine and autocrine effects,

206–207PGT/SLCO2A1 and SLC transporters,

208in vascular and cardiometabolic diseasesω-hydroxylase CYP4 pathway,

244–245CVD, 244lipid intermediary metabolism, 245metabolic conditions, 242mitochondrial function, 245–246NSAIDs, 243prostanglandin synthases, 243–244

visceral and subcutaneous WAT, 234–235

BAT, 235chronic low-grade persistent

inflammation, 238–239CLS, 236HF diet, 235–236hypoxia and HO-2, 237–238MetS, 236–237PUFA, 237

Eicosapentaenoic acid (EPA), 158–159Electrocardiographic monitoring, 26Elongase (Elovl), 158–159, 161, 177–179Elongase 5 (Elovl5), 180–181Elovl. See ElongaseElovl5. See Elongase 5Endoplasmic reticulum (ER), 158–159

Endothelial nitric oxide synthase (eNOS), 199–201

Endotoxin, 89eNOS. See Endothelial nitric oxide synthaseEnoyl-CoA hydratase 3-hydroxyacyl-CoA

dehydrogenase (EHHADH), 229–230EoE. See Eosinophilic esophagitisEosinophil-specific oxidative enzymes, 13Eosinophilic esophagitis (EoE), 140–141EPA. See Eicosapentaenoic acidEPA CYP2-produced epoxyeicosatetrae-

noic acid (EEQ), 199EPA CYP4-produced hydroxyeicosapen-

taenoic acid (19-HEPE), 199–200Epicutaneous sensitization (EC sensitiza-

tion), 135–136Epidermal fatty acid binding proteins

(E-FABPs), 167–168Epoxyeicosatrienoic acid (EET), 179–180,

189ER. See Endoplasmic reticulumERK. See Extracellular signal-regulated

kinaseESBA105 antibody fragment, 61–62Escherichia coli (E. coli), 97–98Etanercept, 58–59, 59tExcretory/secretory (ES) products, 141Exercise-induced bronchoconstriction

model (EIB model), 24Experimental autoimmune

encephalomyelitis (EAE), 280–281Extracellular signal-regulated kinase (ERK),

275

FFA aldehyde dehydrogenase (FALD), 206FA-CoA. See Fatty acid-coenzyme AFABPs. See Fatty acid binding proteinsFADS. See Fatty acid desaturaseFALD. See FA aldehyde dehydrogenaseFarnesoid-X-receptor (FXR), 219FAs. See Fatty acidsFAT/CD36. See Fatty acid translocaseFATP. See Fatty acid transport proteinsFatty acid binding proteins (FABPs),

158–159A-FABP, 168–169ACS activity, 166

319

Index

ACSL and NASH, 168–169E-FABP and N-FABP, 167–168eicosanoids and HNF4α, 172FA transporters, 172–173FABPpm and serum FFAs, 168function and subcellular location,

160f–161fH-FABP, 167L-FABPs and I-FABP, 166–167LCFA FA oxidation, 172nuclear localization region, 171proteins, 173

Fatty acid desaturase (FADS), 161FADS1 geneΔ5 desaturase activity, 179–180Δ6 FADS1 activity, 245expression, 179–180producing PUFAs, 177–179

FADS2 geneencoding Δ6-desaturase, 179–180expression, 179–180producing PUFAs, 177–179

FADS3 gene, 179–180Fatty acid receptors, 213–214Fatty acid translocase (FAT/CD36),

162–163, 168Fatty acid transport proteins (FATPs),

158–159. See also Acyl-CoA binding proteins (ACBPs)

function and subcellular location, 160f–161f

protein family, 163FATP3 and FATP4, 163metabolic homeostasis, 166nomenclature and properties,

164t–165tFatty acid transporters, 162–163

ACBP, 169–170eicosanoids and HNF4α, 172FA and acyl-CoA pools, 170FA transporters, 172–173LCFA FA oxidation, 172in MetS and NAFLD, 170nuclear localization region, 171proteins, 173

cellular uptake of FFAs, 170–171FABPs. See Fatty acid binding proteins

(FABPs)

Fatty acid-coenzyme A (FA-CoA), 158–159

Fatty acids (FAs), 158–159ACS channeling, 173–174ACSL5 expression, 228bioactive, 158–159FATP3 transporting, 163receptors, 213–214transporters, 168uptake role in metabolic homeostasis,

166Fatty liver dystrophy (fld), 177FeNO. See Fractional exhaled nitric oxideFEV1. See Forced expiratory volume in 1

secondFFA. See Free fatty acidFITC. See Fluorescein isothiocyanateFLAP. See 5-lipoxygenase activity proteinfld. See Fatty liver dystrophyFluorescein isothiocyanate (FITC),

135–136Forced expiratory volume in 1 second

(FEV1), 3–4Forkhead box P3 (FOXP3), 132FOXP3. See Forkhead box P3Fractional exhaled nitric oxide (FeNO), 13Free fatty acid (FFA), 158–159FXR. See Farnesoid-X-receptor

GG-protein-coupled eicosanoid receptors

(GPCR), 209Gastrointestinal stromal tumor (GIST), 292GIST. See Gastrointestinal stromal tumorGlucagon-like peptide-1 (GPL-1),

213–214Glucocorticoid (GR), 219Glucose transporter 4 (Glut4), 240Glucose-stimulated insulin secretion

(GSIS), 167–168Glut4. See Glucose transporter 4Glutathione (GSH), 190–191, 207–208Glycerol phosphate acyl transferase (GPAT),

174Glycosylphosphatidylinositol (GPI), 84–85Golimumab, 59tGPAT. See Glycerol phosphate acyl

transferase

Index320

GPCR. See G-protein-coupled eicosanoid receptors

GPI. See GlycosylphosphatidylinositolGPL-1. See Glucagon-like peptide-1GR. See GlucocorticoidGraft-versus-host disease (GvHD), 66,

269–270Graft-versus-leukemia (GvL), 281–282GSH. See GlutathioneGSIS. See Glucose-stimulated insulin secretionGvHD. See Graft-versus-host diseaseGvL. See Graft-versus-leukemia

HH-FABPs. See Heart and skeletal fatty acid

binding proteinsHDL. See High-density lipoproteinHeart and skeletal fatty acid binding

proteins (H-FABPs), 167Heme oxygenase-2 (HO-2), 237–238Heparin sulfate proteoglycan (HSPG), 182Hepatic steatosis, 226Hepatocyte nuclear factor 4α (HNF4α),

169–17019-HEPE. See EPA CYP4-produced

hydroxyeicosapentaenoic acidHepoxilins (HX), 195–196HETE. See Hydroxyeicosatetraenoic acid20-HETE. See AA CYP4-produced

hydroxyeicosatetraenoic acidHF diet. See High-fat dietHigh-density lipoprotein (HDL), 84,

182–183High-fat diet (HF diet), 168–169

induction of CYP4A genes by, 202f–203fHinge/V3 domain, 271–27212-HHT. See 12-Hydroxyeicosatrienoic

acidHNF4α. See Hepatocyte nuclear factor 4αHNF4α/NR4A1 regulator, 222HNR. See Hormone nuclear receptorHO-2. See Heme oxygenase-2HODE. See 9-Hydroxyoctadecadienoic acidHormone nuclear receptor (HNR), 167–168

eicosanoid regulationHNR family, 219LRH-1, 222

HH

HHHH

macrophages and dendritic cells, 223metabolic sensors, 219–220NAFLD, 218–219NR4A2/NURRI, 222–223NR4H4, 222PPARα, 220PPARβ, 220–221PPARγ, 221treatment of metabolic diseases,

221–222mechanism of regulation, 210t–212tormone-sensitive lipase (HSL), 167PETE. See Hydroperoxyeicosatetraenoic

acidPV. See Human papilloma virusSL. See Hormone-sensitive lipaseSPG. See Heparin sulfate proteoglycanuman asthma biologyairway inflammation biomarkers,

12–13blood eosinophil counts, 13–14eosinophil-specific oxidative enzymes,

13FeNO and iNOS, 13ICS dose, 14–15soluble blood biomarkers, 14

airway inflammationcorticosteroids effects on, 8inflammatory cytokines, 5–7

asthma biomarkers, 11PD biomarkers, 12predictive biomarkers, 11–12prognostic biomarkers, 12surrogate biomarkers, 12

asthma heterogeneitydisconnection between, 10fgranulocytic infiltration, 9–11type 2 inflammation, 8–9

biomarker-guided clinical trial design, 29therapies targeting IgE, 29–32therapies targeting IL4, IL13, 32–35therapies targeting IL5, 32therapies targeting IL9 and TNFα,

35–36clinical features

bronchial asthma, 3–4eczematous skin inflammation, 4

Index 321

clinical study phasesallergen challenge model, 23–24EIB model, 24electrocardiographic monitoring, 26healthy volunteers, 23IND approach, 21–22MEDI-528, 25pilot study, 23proof-of-concept study, 25–26safety and TGN1412, 22single-dose exposures, 23therapeutics, 22–23

mediators of type 2 inflammation, 7foutcome measures

ACC tool, 28airflow obstruction, 27–28asthma severity, 28–29bronchodilation and FEV1, 27treatment, 28

pharmacokinetics and pharmacodynamicsdosing, 15–17PD biomarkers and linkage, 21pharmacodynamic biomarkers,

17–21standard-of-care asthma therapy, 4–5

Human Ca2+-independent iPLA2, 184Human papilloma virus (HPV), 109HX. See HepoxilinsHydroperoxyeicosatetraenoic acid

(HPETE), 193–194Hydroxyeicosatetraenoic acid (HETE), 189,

192–197, 20012-Hydroxyeicosatrienoic acid (12-HHT),

1929-Hydroxyoctadecadienoic acid (HODE),

195–19615-Hydroxy prostaglandin dehydrogenase

(15-PGDH), 205–206

II-FABPs. See Intestinal fatty acid binding

proteinsI/R injury. See Ischemia/reperfusion injuryIADRs. See Idiosyncratic adverse drug

reactionsIBD. See Inflammatory bowel diseaseICS. See Inhaled corticosteroid

Idiosyncratic adverse drug reactions (IADRs), 224–225

in sepsis and inflammation, 225IEC. See Intestinal epithelial cellIFN-inducible protein-10 (IP-10), 88–89IGH. See Immunoglobulin heavy chainIL. See InterleukinIL-1 receptor-associated kinase (IRAK), 88IL-7Rα. See Interleukin-7 receptor alphaImmune complexes, 60–61Immune system, 268–269Immunoglobulin heavy chain (IGH), 143–144Immunological synapse (IS), 282Immunosuppressive drugs, 277IND approach. See Investigational new

drug approachInducible nitric oxide synthase (iNOS), 13Inflammation, 3–4Inflammatory bowel disease (IBD), 64,

140–141Inflammatory cytokines

Th2 cytokines, 5–6type 2 alarmins, 6–7

Infliximab, 58–59, 59tInhaled corticosteroid (ICS), 4–5

effects on airway inflammation, 8Innate immune cells, 133–134iNOS. See Inducible nitric oxide synthaseInsig. See Insulin-induced geneInsulin receptor (IR), 176–177Insulin receptor substrate-1 (IRS-1),

176–177Insulin-induced gene (Insig), 169–170Interferon regulatory factors (IRF), 88–89Interleukin (IL), 5–6, 63–64, 167Interleukin-7 receptor alpha (IL-7Rα),

130–131SNPs in, 145

Intestinal epithelial cell (IEC), 132Intestinal fatty acid binding proteins

(I-FABPs), 166–167Intestinal inflammation

using DSS and NE, 141–142EoE and IBD, 140–141gastrointestinal system, 142mRNA levels, 140TH2- and TH1-type inflammation, 141

Index322

Intracellular iPLA2, 183–184Intravenous route (IV route), in mAb

therapeutics, 15Investigational biologic asthma therapies, 30tInvestigational new drug approach (IND

approach), 21–22IP-10. See IFN-inducible protein-10IR. See Insulin receptorIRAK. See IL-1 receptor-associated kinaseIRF. See Interferon regulatory factorsIRS-1. See Insulin receptor substrate-1IS. See Immunological synapseIschemia/reperfusion injury (I/R injury),

199

JJanus protein tyrosine kinase (JAK),

130–131JNK. See c-Jun N-terminal kinase

K2-Keto-3-deoxyoctonate (KDO), 9915-Keto prostaglandin Δ13 reductase

(13-PGR), 205–206Kinapse, 285–286

LL-FABPs. See Liver fatty acid binding

proteinsL-PGDS. See Lipocalin-type PGD synthaseLA. See Linolenic acidLABA. See Long-acting β2-adrenergic

agonistLangerhans cell (LC), 135–136LAR. See Late-phase allergic responseLate-phase allergic response (LAR), 29–31LBPs. See LPS-binding proteinsLC. See Langerhans cellLCFA. See Long-chain fatty acidLDL. See Low-density lipoproteinLDLR. See Low-density lipoprotein

receptorLDs. See Lipid dropletsLegionella pneumophila, 94–95LEKTI. See Lymphoepithelial Kazal-type-

related inhibitorLeucine-rich repeat proteins (LRR

proteins), 84–85

Leukotriene (LT), 159catabolism

bioactive eicosanoids, 204EETs, sEH and hepoxilin, 204–205hydroxyl eicosanoids, 20615-PGDH and 13-PGR, 205–206

receptors, 216–217synthesis in intermediary metabolismβ-cell insulin and α-cell glucagon,

196–197Alox5 gene, 194–195CYP and LT metabolites, 194HX and 12/15-LOX expression, 196inflammation and hepatocyte survival,

19512/A5-LOX, 195–1965-LOX, 194LTs, LX and HPETE, 193–194

Leukotriene receptor antagonist (LTA), 4–5Linolenic acid (LA), 158–159Lipid A, 90

diversity in natureBacteroides thetaiotaomicron, 93–94Francisella novicida, 96Gram-negative bacterial LPS, 92–93Legionella pneumophila, 94–95LPS-dependent innate response,

95–96pathogenic bacteria, 93structures isolation, 94fvascular ulceration, 93

endotoxic principleE. coli and S. minnesota, 92fraction A, 90–92Gram-negative LPS, 91fLPS with TCA, 90–92

synthesis, 96aminoalkyl glucosaminide 4-phos-

phates, 106–109Escherichia coli lipid A analogs, 97–98lipid A analogs, 103–104synthetic monophosphoryl lipid A,

104–106Lipid droplets (LDs), 158–159

ACSL3, 173–174biogenesis, 209cytosolic cPLA2IVA localization, 184formation in pancreas and liver, 213

Index 323

Lipid IVa, 95fantagonist structure, 102–103dimer interface, 102human PBMC, 99human PMN cells, 99hydrophobic interactions, 102KDO synthesis, 99MD-2, 100–102mouse–human or chimeric coreceptors,

100–101murine TLR4/MD-2 receptor complex,

100mutagenesis data, 101TLR4/MD-2 receptor complex, 100

Lipid rafts, 286Lipocalin-type PGD synthase (L-PGDS),

191–192Lipopolysaccharide receptor (LPS receptor),

82lipid A, 90principal structural domains, 90using TCA or organic solvents, 90

Lipoxins (LX), 16212/15-Lipoxygenase (12/15-LOX),

195–196implication in MetS and NAFLD,

196–197overexpression effect in mice, 196

12-Lipoxygenase (12-LOX), 193–194forms, 195–196

12/A5-Lipoxygenase (12/A5-LOX), 195–196

5-Lipoxygenase (5-LOX), 1945-Lipoxygenase activity protein (FLAP), 194Lipoxygenase (LOX), 159Liver fatty acid binding proteins (L-FABPs),

166–167Liver-related homolog (LRH), 219Liver-related homolog-1 (LRH-1), 222Liver-X-receptor (LXR), 167Long-acting β2-adrenergic agonist (LABA),

4–5Long-chain acyl-CoA synthetase (ACSL),

168–169, 173–174Long-chain fatty acid (LCFA), 166Low-density lipoprotein (LDL), 166Low-density lipoprotein receptor (LDLR),

166

12/15-LOX. See 12/15-Lipoxygenase12-LOX. See 12-Lipoxygenase5-LOX. See 5-LipoxygenaseLOX. See LipoxygenaseLPA. See Lysophosphatidic acidLPCAT. See Lysophosphatidylcholine

acyltransferaseLPS receptor. See Lipopolysaccharide

receptorLPS receptor complex

CD14, 84–85amino glycolipids, 86benzylammonium lipids, 86S-LPS and R-LPS, 85TLR4 and MD-2, 85TLR4/MD-2/LPS complexes, 86TRIF-dependent signaling pathway, 85

TLR4/D-2, 86–87agonist/antagonist activity, 87hydrophobic and electrostatic

interactions, 87–88MD-2, 87

LPS-binding proteins (LBPs), 83–84BPI and PLTP, 84MyD88- and TRIF-dependent pathway

signaling, 83fplasma lipoproteins, 84

LRH. See Liver-related homologLRH-1. See Liver-related homolog-1LRR proteins. See Leucine-rich repeat

proteinsLT. See Leukotriene. See also LymphotoxinLTA. See Leukotriene receptor antagonistLTA4 hydrolase, 194LTB4–12-hydroxy dehydrogenase. See

13-PGRLTC4 synthase, 195LTα. See Lymphotoxin-αLX. See LipoxinsLXR. See Liver-X-receptorLXRα/NRIH3 cholesterol sensor, 222Lymphoepithelial Kazal-type-related

inhibitor (LEKTI), 134Lymphotoxin (LT), 53Lymphotoxin-α (LTα), 54LysoPC. See LysophosphatidylcholineLysophosphatidic acid (LPA), 174–175,

217–218

Index324

Lysophosphatidylcholine (LysoPC), 175–176

Lysophosphatidylcholine acyltransferase (LPCAT), 173–177, 181, 217–218

Lysosome PLA2 family, 187–188

MmAb. See Monoclonal antibodyMajor histocompatibility complex (MHC),

53, 272–273Malondialdehyde (MDA), 192MALT1. See Mucosa-associated lymphoid

tissue-1MAP kinase phophatase-1 (MKP-1), 111MAPK. See Mitogen-activated protein

kinaseMAPK-activated protein kinase 2, 55MCD. See Methionine-choline dietMCP. See Monocyte chemotactic proteinMD-2 coreceptor, 87MDA. See MalondialdehydemDC. See Myeloid-derived dendritic cellMechanism of action (MOA), 16–17MEDI-528, 25Mesenchymal stem cell (MSC), 237–238Metabolic sensors, 219–220Metabolic syndrome (MetS), 161, 188–189

diseases, 226visceral and subcutaneous WAT,

234–235eicosanoids

in adipocyte metabolism and obesity, 239–240

in diabetes and insulin resistance in pancreas, 240–242

in NAFLD and obesity, 226–234in vascular and cardiometabolic

diseases, 242–246molecular mechanism, 209

eicosanoid G-protein-coupled receptors, 214–218

eicosanoid regulation, 218–223fatty acid receptors, 213–214

prostaglandins and leukotrienes catabolism

bioactive eicosanoids, 204EETs, sEH and hepoxilin, 204–205

hydroxyl eicosanoids, 20615-PGDH and 13-PGR, 205–206

prostaglandins synthesis, 189–190eicosanoids, 197–204leukotrienes synthesis, 193–197

transport and transcellular metabolismhuman ABC transporters, 207MRP1/ABCC1, 207–208NAFLD, 208–209paracrine and autocrine effects,

206–207PGT/SLCO2A1 and SLC transport-

ers, 208TX, EET and HETE, 189

Methionine-choline diet (MCD), 228MetS. See Metabolic syndromeMHC. See Major histocompatibility

complexMicrosomal PGES1 (mPEGS-1), 190–191Microsome transfer protein (MTP), 177,

194–195Mitogen-activated protein kinase (MAPK),

111, 275MKP-1. See MAP kinase phophatase-1MOA. See Mechanism of actionMolecular mechanism, 209

eicosanoid G-protein-coupled receptors, 214–218

eicosanoid regulation, 218–223fatty acid receptors, 213–214

Monoclonal antibody (mAb), 4–5, 67–68Monocyte chemotactic protein (MCP), 217Monophosphoryl lipid A (MPLA), 104, 109

HPV, 109MPLA, 110MyD88-dependent signaling, 110–111TLR4-dependent innate immune

response, 109–110Monounsaturated fatty acids (MUFAs),

226–227mPEGS-1. See Microsomal PGES1MPLA. See Monophosphoryl lipid AMRP/ABC transporters, 207MRP1/ABCC1 transporter, 207–208MRP4. See Multidrug resistance

protein 4MS. See Multiple sclerosis

325

Index

MSC. See Mesenchymal stem cellMTP. See Microsome transfer proteinMucosaassociated lymphoid tissue-1

(MALT1), 274–275MUFAs. See Monounsaturated fatty acidsMultidrug resistance protein 4 (MRP4),

190–191Multiple sclerosis (MS), 56, 144–145Murine TLR4/MD-2 receptor complex,

100Myeloid-derived dendritic cell (mDC), 132

NN-FABPs. See Neuronal fatty acid binding

proteinsNAFLD. See Nonalcoholic fatty liver

diseaseNASH. See Nonalcoholic steatohepatitisNational Institutes of Health (NIH), 11Natural killer cell (NK cell), 54–55,

130–131, 272Natural killer T cell (NKT cell), 282NE. See Neutrophil elastaseNetherton syndrome (NS), 134Neuronal fatty acid binding proteins

(N-FABPs), 167–168Neutrophil elastase (NE), 141–142NF-κB. See Nuclear factor kappa BNFAT. See Nuclear factor of activated T

cellsNIH. See National Institutes of HealthNitric oxide (NO), 13NK cell. See Natural killer cellNKT cell. See Natural killer T cellNO. See Nitric oxideNOD mouse model. See Nonobese

diabetic mouse modelNonalcoholic fatty liver disease (NAFLD),

161therapies in treatment, 246

EPA/DHA, 247NASH, 246pharmaceutical therapies, 246–247

Nonalcoholic steatohepatitis (NASH), 168–169, 226

Nonobese diabetic mouse model (NOD mouse model), 241–242

Nonspecific resistance models (NSR models), 108–109

Nonsteroidal antiinflammatory drug (NSAID), 178f–179f, 189–190

in inducing 15-PGDH, 205–206in inhibiting COX-2, 205–206

Novel protein kinase C (nPKC), 270–271nPKC. See Novel protein kinase CNR. See Nuclear receptorNR4H4. See Nuclear family 4 subgroup A

receptorsNS. See Netherton syndromeNSAID. See Nonsteroidal antiinflammatory

drugNSR models. See Nonspecific resistance

modelsNuclear factor kappa B (NF-κB), 134–135,

272–273Nuclear factor of activated T cells (NFAT),

272–273Nuclear family 4 subgroup A receptors

(NR4H4), 222Nuclear receptor (NR), 170–171

OO-antigen chain, 90O-polysaccharide, 90OAT. See Organic anion transporterOCS. See Oral corticosteroidOff label investigations, 64–65Omalizumab, 15–16, 29–31Omega hydroxylase pathways

eicosanoidsantiinflammatory eicosanoids,

198f–199fCYP and CYP2 enzymes, 197–199CYP2C and CYP4 pathways, 197CYP2C epoxygenase and CYP4 ω-hydroxylase, 201–204

CYP4A and CYP2C P450s function, 202f–203f

FA ω-hydroxylase family, 200human CYP4A11 ω-hydroxylase,

200–201human epoxygenase and EETs, 199hydroxylates DHA, 201ω-3 PUFAs, EPA and DHA, 199–200

326 Index

Omega-3PUFA (ω3-PUFA), 189–190antiinflammatory, 189–190dietary ingestion, 188–189enteral, 223–224GPR120 activation, 213–214

Oral corticosteroid (OCS), 4–5Organic anion transporter (OAT), 206–207Ovalbumin (OVA), 135–136OX40 ligand (OX40L), 132

DC costimulatory molecules, 142–143TSLP-induced DC expression, 138

Oxooctadecadienoic acid (oxoODE), 226–227

PPA. See Phosphatidic acidPAF. See Platelet activating factorPAF-AH. See Platelet activating factor

acetylhydrolasesPAP. See Phosphatidic acid phosphatasePAP/LP. See sn-3-phosphatide phosphohy-

drolasePAR-2. See Protease-activated receptor 2Patatin, 184Patatin-like phospholipase domain

containing lipase (PNPLA), 182PBMC. See Peripheral blood mononuclear

cellPC. See PhosphatidylcholinePD biomarkers. See Pharmacodynamic

biomarkersPE. See PhosphatidylethanolaminePeripheral blood mononuclear cell

(PBMC), 99Peripheral supramolecular activation cluster

(pSMAC), 283–284Peroxisome proliferator activated receptor

(PPAR), 167Peroxisome proliferator activated receptor

coactivator (PGC), 175PG. See ProstaglandinPGC. See Peroxisome proliferator activated

receptor coactivatorPGD synthase (PGDS), 191–192PGD2, 191–19215-PGDH. See 15-Hydroxy prostaglandin

dehydrogenasePGDS. See PGD synthase

PPPP

PP1

PP

PPPPPPPPP

GE-1 synthase (PGES1), 190–191GES1. See PGE-1 synthaseGG2. See Protaglandin peroxidaseGHS. See Prostaglandin endoperoxide H

synthaseGI2. See ProstacyclinGIS. See Prostacyclin synthase3-PGR. See 15-Keto prostaglandin Δ13

reductaseGT. See Prostaglandin transporterharmacodynamic biomarkers (PD

biomarkers), 12, 17–18anti-IL13 antibodies, 17–18anti-IL5 and anti-IL13, 20–21direct target binding assays, 20FeNO and serum periostin levels, 19–20and linkage to clinical end points, 21MOA-related biomarkers, 19–20omalizumab, 18–19

harmacokinetic (PK), 2–3hosphatidic acid (PA), 158–159hosphatidic acid phosphatase (PAP), 175hosphatidylcholine (PC), 158–159, 163hosphatidylethanolamine (PE), 158–159hosphatidylinositol (PI), 158–159hosphatidylinositol 3-kinase (PI3K), 285hosphatidylserine (PS), 158–159hospholipase A2 (PLA2), 245–246role in formation of bioactive lipids

AA incorporation into membrane, 181classical independent iPLA2IVA, 184–185cytosolic cPLA2IVA-null mice, 184eicosanoid and intermediary

metabolism, 188FFAs and LPC, 183HSPG-dependent and independent

pathways, 182human Ca2+-independent iPLA2, 184independent iPLA2IVA, 185–186intracellular iPLA2, 183–184lysosome PLA2 family, 187–188in MetS, 182PAF-AH family members, 187PLA2 functions, 181–182PNPLA2 and PNPLA3 enzymes,

186–187sPLA2 and atherosclerosis, 182–183sPLA2, cPLA2 and iPLA2, 182

Index 327

Phospholipase C (PLC), 158–159Phospholipase C-©1 (PLC-©1), 272–273Phospholipid (PL), 158–159Phospholipid transfer protein (PLTP), 84Phospholipidase A1 (PLA 1), 158–159PI. See PhosphatidylinositolPI3K. See Phosphatidylinositol 3-kinasePitrakinra, 15PK. See PharmacokineticPKA. See Protein kinase APKC. See Protein kinase CPKCθ. See Protein kinase C-thetaPL. See PhospholipidPLA 1. See Phospholipidase A1PLA2. See Phospholipase A2Plasma lipoproteins, 84Plasma membrane lipids (PM lipids), 283–284Platelet activating factor (PAF), 182Platelet activating factor acetylhydrolases

(PAF-AH), 182family members, 187

PLC. See Phospholipase CPLC-©1. See Phospholipase C-©1PLTP. See Phospholipid transfer proteinPM lipids. See Plasma membrane lipidsPMN cell. See Polymorphonuclear cellPNPLA. See Patatin-like phospholipase

domain containing lipasePNPLA8. See Independent iPLA2IVAPNPLA9. See Classical independent

iPLA2IVAPolymorphonuclear cell (PMN cell), 99Polyunsaturated fatty acids (PUFAs),

158–159, 160f–161fPPAR. See Peroxisome proliferator

activated receptorPredictive biomarkers, 11–12Pregnane-X-receptor (PXR), 219Prkcq−/− mice, 273–274Prognostic biomarkers, 12Prostacyclin (PGI2), 189–191Prostacyclin synthase (PGIS), 191Prostaglandin (PG), 159

catabolismbioactive eicosanoids, 204EETs, sEH and hepoxilin, 204–205hydroxyl eicosanoids, 20615-PGDH and 13-PGR, 205–206

synthesis in intermediary metabolismCOX1 and COX2, 190EP3 and EP4, 190–191NADH and NADPH, 192–193PG and TXs, 189–190PGD2, 191–192PGF synthase, 192PGI2 and VSM cells, 191

Prostaglandin endoperoxide H synthase (PGHS), 189–190

Prostaglandin transporter (PGT), 205–206, 208

Prostaglandins and leukotrienes catabolismbioactive eicosanoids, 204EETs, sEH and hepoxilin, 204–205hydroxyl eicosanoids, 20615-PGDH and 13-PGR, 205–206

Protaglandin peroxidase (PGG2), 189–190Protease-activated receptor 2 (PAR-2),

134–135Protein kinase A (PKA), 194Protein kinase C (PKC), 176–177, 270

C-terminal catalytic domain, 270–271N-terminal regulatory domain, 270–271

Protein kinase C-theta (PKCθ), 269–270C-terminal catalytic domain, 270–271CD28 costimulation, 287–288cellular receptors for phorbol esters, 271chromosomal mapping, 271–272function in treg development

in maintaining immune homeostasis, 288

nTregs and NF-κB, 288–289prkcq−/− T cells or wild-type T cells,

290in Teff cells, 290–291Treg–APC interface, 289–290

in hematopoietic cells, 272in human disease

Ewing’s sarcoma, 292–293GIST, 292insulin resistance, 293prkcq−/− mice, 291SNPs, 291–292VDR-binding site, 291–292

and immunological synapseantireceptor antibodies, 287APCs and PM lipids, 283–284

Index328

Protein kinase C-theta (PKCθ) (Continued )IS and cSMAC localization, 285lipid rafts, 286PLCγ-mediated hydrolysis, 284–285stable IS and kinapse, 285–286stable pSMAC, 286

N-terminal regulatory domain, 270–271promising drug target

AEB071, 295–296AP-1 and NF-κB, 294ATP competitive inhibitors, 295phase II AEB071 clinical trial,

296–297small molecule kinase inhibitors, 297T cell immunosuppression, 293therapeutic effects, 294–295

role in immune responsesallogeneic BMT and GvHD, 281–282cardiac allograft rejection, 281Prkcq−/− mice and ConA-induced

acute hepatitis, 282–283proliferation and IL-2 production, 277selectivity functions in vivo, 278t–279tTh1 and TLR, 277–280Th2-mediated immune responses,

280–281tumor cells and virus-infected cells,

282serine/threonine kinases, 270specialized functions

activation-induced cell death, 275–276Bcl10–MALT1 complex, 274–275CARD, 274–275ChIP-on-ChIP assay, 276JNK and MAP kinases, 275prkcq−/− mice and T cells, 273–274in TCR-mediated T cell activation,

272–273transcription factor AP-1, 273

T cell anergy, 287two-signal hypothesis, 287–288

PS. See PhosphatidylserinePsA. See Psoriatic arthritispSMAC. See Peripheral supramolecular

activation clusterPsoriasis, 56Psoriatic arthritis (PsA), 56

PUFAs. See Polyunsaturated fatty acidsPXR. See Pregnane-X-receptor

RR-LPS. See Rough LPSRA. See Rheumatoid arthritisRAR. See Retinoic acid receptorRAR-related orphan receptor (ROR), 219Reactive oxygen species (ROS), 226Receptor-based drugs

primary mechanism of actionADCC, 61antidrug antibody response, 61ESBA105, 61–62immune complexes, 60–61intact IgG1, 60pharmacokinetics, 60treceptor-binding region, 59–60

TNF inhibitors, 57certolizumab, 58–59characteristics, 59tIgG1 antibody, 57–58TNF and LTα cytokine system, 58f

Receptor-interacting protein 1 (RIP1), 88–89Regulatory T cells (Tregs), 132, 268–269Respiratory diseases

aberrant lung expression, 139allergic airway disease, 136–137COPD and BAL, 136–137mouse models, 137–138parenchymal cells and immune cells, 139sensitization/priming stage, 138

Retinoic acid receptor (RAR), 219Retinoid X receptor (RXR), 134–135, 219Rheumatoid arthritis (RA), 56, 144–145,

289–290RIP1. See Receptor-interacting protein 1ROR. See RAR-related orphan receptorROS. See Reactive oxygen speciesRough LPS (R-LPS), 85RXR. See Retinoid X receptor

SS-LPS. See Smooth chemotypes of LPSS. minnesota diphosphoryl lipid A (sDLA),

111S. minnesota MPLA (sMLA), 111

Index 329

SABA. See Short-acting β2-adrenergic agonist

SAC. See Secondary acyl chainSAE. See Serious adverse eventSalmonella minnesota MPLA

caspase-1, 112MAPK pathway, 111MyD88-dependent signaling, 111–112sDLA and sMLA, 111

SAT. See Subcutaneous adipose tissueSaturated fatty acids (SFAs), 168SC route. See Subcutaneous routeSCD. See Stearoyl-CoA desaturaseSCFA. See Short-chain FAsDLA. See S. minnesota diphosphoryl

lipid ASecondary acyl chain (SAC), 99Secretory leukocyte peptidase inhibitor

(SLPI), 141–142sEH. See Soluble epoxide hydrolaseSeptic shock

LBP, 84LPS, 89

Serine peptidase inhibitor Kazal-type 5 gene (SPINK5 gene), 134

Serious adverse event (SAE), 25Serum alanine aminotransferase (ALT),

233–234Serum lipocalin PGD synthase, 243–244Serum periostin, 14SFAs. See Saturated fatty acidsSH2-domain containing inositol

phosphatase-1 (SHIP-1), 111–112Sheep red blood cells (SRBC), 98SHIP-1. See SH2-domain containing

inositol phosphatase-1Short heterodimer partner (SHP), 219Short-acting β2-adrenergic agonist (SABA),

4–5Short-chain FA (SCFA), 168SHP. See Short heterodimer partnerSHP/NROB2 receptor, 222Single nucleotide polymorphism (SNP),

32–33, 134, 180–181, 291–292SIRS. See Systemic inflammatory response

syndromeSjögren syndrome (SS), 62–63

Skin disordersallergic skin inflammation, 135–136atopic dermatitis, 134atopic march and AR, 136RXRs and SPINK5 gene, 134–135

SLC. See Solute ligand carrierSLE. See Systemic lupus erythematousSLPI. See Secretory leukocyte peptidase

inhibitorSMAC. See Supramolecular activation

clustersMLA. See S. minnesota MPLASmooth chemotypes of LPS (S-LPS), 85sn-3-phosphatide phosphohydrolase (PAP/

LP), 175SNP. See Single nucleotide polymorphismSoluble blood biomarkers, 14Soluble epoxide hydrolase (sEH), 199, 242Solute ligand carrier (SLC), 162–163

and ABC efflux transporter, 208SPC. See Surfactant protein CSPINK5 gene. See Serine peptidase

inhibitor Kazal-type 5 geneSRBC. See Sheep red blood cellsSREBP2. See Sterol regulatory element

binding protein 2SS. See Sjögren syndromeStandard-of-care asthma therapy, 4–5Stearoyl-CoA desaturase (SCD), 179–180Sterile inflammation, 57Sterol regulatory element binding protein 2

(SREBP2), 169–170Streptozocin (STZ), 242STZ. See StreptozocinSubcutaneous adipose tissue (SAT),

234–235BAT, 235CLS, 236HF diet, 235–236hypoxia and HO-2, 237–238low-grade persistent inflammation,

238–239MetS, 236–237PUFA, 237

Subcutaneous route (SC route), 15Supramolecular activation cluster (SMAC),

283–284

Index330

Surfactant protein C (SPC), 137–138Surrogate biomarkers, 12Synthetic lipid A, 96

AGPs, 106chemical and metabolic stability,

108–109crystal structure, 109intravenous administration, 108modifications, 106–108SACs, 108structures, 106, 107f

chemical structure, 96–97E. coli lipid A analogs, 97–98

BSA and SRBC, 98IL-1 α/β induction, 98inflammatory or endotoxic activity,

98lipid A analogs

diglucosamine backbone, 103endotoxic activity, 104non-reducing halves, 103–104pathophysiological endotoxic

properties, 103lipid IVa

antagonist structure, 102–103dimer interface, 102human PBMC, 99human PMN cells, 99hydrophobic interactions, 102KDO synthesis, 99MD-2, 100–102mouse–human or chimeric

coreceptors, 100–101murine TLR4/MD-2 receptor

complex, 100mutagenesis data, 101structure, 95fTLR4/MD-2 receptor complex, 100

LPS, 96monophosphoryl lipid A

detoxified lipid A analogs, 104SACs, 105–106synthetic MPL congeners, 105tetra- and penta-acyl species, 104–105

Osaka group, 97Systemic inflammatory response syndrome

(SIRS), 223–224Systemic lupus erythematous (SLE), 62–63

TT cell anergy, 287T cell receptor (TCR), 269–270T lymphocytes, 132–133, 269–270T1D. See Type 1 diabetesT1DM. See Type I diabetes mellitusT2DM. See Type II diabetes mellitusT538. See Thr-538TAG. See TriacylglycerolTCA. See TrichloroaceticacidTCR. See T cell receptorTeff. See Effector T cellTGF. See Transforming growth factorTGN1412, 22Th1. See Type 1 helper TTH2 chemokines, 138Thiazolidinedione (TZD), 173–174Thr-538 (T538), 271–272, 285Thromboxane (TX), 189Thromboxane synthase (TXAS), 159Thromoboxane B2 (TXB2), 192Thymic stromal lymphopoietin (TSLP),

5–6, 130signaling, 131TSLP-associated diseases, 134

autoimmune diseases and tolerance issues, 144–145

cancer, 142–144intestinal inflammation, 140–142respiratory diseases, 136–139skin disorders, 134–136

TSLP-responsive cells, 131–132B lymphocytes, 133dendritic cells, 132innate immune cells, 133–134T lymphocytes, 132–133

TSLPR, 130–131Thymic stromal lymphopoietin receptor

(TSLPR), 130–131TIR. See Toll/interleukin-1 receptorTIR domain-containing adaptor protein

(TIRAP), 88TIRAP. See TIR domain-containing

adaptor proteinTLR. See Toll-like receptorTLR4 signaling, 86–87

TLR4/MD-2 complex, 88TRAM/TICAM-2, 88–89

Index

TLR4/D-2 receptor complex, 86–87agonist/antagonist activity, 87hydrophobic and electrostatic

interactions, 87–88MD-2, 87

TLR4/MD-2 receptor complex, 100TNF. See Tumor necrosis factorTNF inhibitors, 57

certolizumab, 58–59characteristics, 59tclinical indications for, 62tefficacy, 62

anti-TNF in CD, 64autoimmune diseases, 62–63disparity in efficacy, 64heterogeneity of response, 63–64

IgG1 antibody, 57–58off label investigations, 64–65pharmacogenetics

demyelinating disorders, 65–66GVHD, 66large-scale genetic analysis, 65TNF and cytokines, 65

pharmacokinetics, 60tTNF and LTα cytokine system, 58f

TNF receptor superfamily (TNFRSF), 52–53. See also Tumor necrosis factor superfamily (TNFSF)

characteristics as drug target, 53LT-alpha and LT-beta, 53LTα, 54TNFR1 and TNFR2, 53–54

TNF bioavailability, 55lymphocytes and macrophages,

55–56TNF expression in human disease, 56

disease associations of polymorphic variants, 57t

in plasma and biological fluids, 56polymorphisms, 56

TNF metabolism, 54TNF biosynthesis, 55toll-like receptor and NK cells,

54–55transmembrane form, 54

TNF-receptor-associated factor (TRAF), 52–53, 114

TNF-related cytokines, 52–53

331

TNFRSF. See TNF receptor superfamilyTNFSF. See Tumor necrosis factor

superfamilyTNFα. See Tumor necrosis factor (TNF)Toll-like receptor (TLR), 82, 144–145,

195–196, 277–280agonists, 82–83mammalian, 82

Toll/interleukin-1 receptor (TIR), 85TRAF. See TNF-receptor-associated factorTRAM. See TRIF-related adaptor

moleculeTransforming growth factor (TGF), 192Transport and transcellular metabolism

human ABC transporters, 207MRP1/ABCC1, 207–208NAFLD, 208–209paracrine and autocrine effects, 206–207PGT/SLCO2A1 and SLC transporters,

208Tregs. See Regulatory T cellsTriacylglycerol (TAG), 158–159

DAG and DGAT1, 175fatty acid transport and channeling, 174free AA cell pool, 175–176GPAT isoforms, 174IRS-2 in insulin resistance, 177LPA and AGPAT, 174–175PAP/LP, 175TAG and PL metabolic pathways,

176–177Trichloroaceticacid (TCA), 90TRIF-related adaptor molecule (TRAM),

88–89TRIF-selective signaling

CRX-547, 112–113comparison, 113fin Kagan model, 114stereochemical change in, 113stimulus trafficking, 114TRAF3, 114TRIF-dependent pathway, 115

monophosphoryl lipid A, 109HPV, 109MPLA, 110MyD88-dependent signaling, 110–111TLR4-dependent innate immune

response, 109–110

332

TRIF-selective signaling (Continued )Salmonella minnesota MPLA

caspase-1, 112MAPK pathway, 111MyD88-dependent signaling, 111–112sDLA and sMLA, 111

TSLP. See Thymic stromal lymphopoietinTSLP knockout (TSLP KO), 141–142TSLP KO. See TSLP knockoutTSLP-associated diseases, 134. See also

Respiratory diseasesautoimmune diseases

immune tolerance, 145overexpression, 144RA and MS, 144–145SNPs, 145

cancer, 142–143solid tumors, 143–144TH2 cytokines promote disease, 143TSLP and TSLP signaling pathways,

144intestinal inflammation

using DSS and NE, 141–142EoE and IBD, 140–141gastrointestinal system, 142mRNA levels, 140TH2- and TH1-type inflammation,

141skin disorders

allergic skin inflammation, 135–136atopic dermatitis, 134atopic march and AR, 136RXRs and SPINK5 gene, 134–135

TSLP-responsive cell, 131–132. See also Dendritic cell (DC)

B lymphocytes, 133innate immune cells, 133–134T lymphocytes, 132–133

TSLPR. See Thymic stromal lymphopoietin receptor

Tumor necrosis factor (TNF), 5–6, 52, 191. See also TNF receptor superfamily (TNFRSF)

bioavailability, 55lymphocytes and macrophages, 55–56

characteristics as drug targetLT-alpha and LT-beta, 53

Index

LTα, 54TNFR1 and TNFR2, 53–54

expression in human diseasedisease associations of polymorphic

variants, 57tin plasma and biological fluids, 56polymorphisms, 56

metabolismTNF biosynthesis, 55toll-like receptor and NK cells, 54–55transmembrane form, 54

Tumor necrosis factor superfamily (TNFSF), 52

targeting TNFSF pathwaysbelimumab and denosumab, 66–67human disease linkage, 67tHVEM pathways, 67TNF-LT-LIGHT network, 67–68

TNF superfamily systems, 69t–70tTwo-signal hypothesis, 287–288TX. See ThromboxaneTXAS. See Thromboxane synthaseTXB2. See Thromoboxane B2Type 1 diabetes (T1D), 291–292. See also

Type I diabetes mellitus (T1DM)Type 1 helper T (Th1), 277–280Type 2 myeloid (T2M) cells, 5–6Type I diabetes mellitus (T1DM), 242Type II diabetes mellitus (T2DM),

179–180TZD. See Thiazolidinedione

UUlcerative colitis (UC), 140–141Unsaturated fatty acids (uSFAs), 158–159uSFAs. See Unsaturated fatty acids

VVaccination, 105–106Vascular endothelial growth factor (VEGF),

190–191Vascular smooth muscle cells (VSM cells),

191VAT. See Visceral adipose tissueVDR. See Vitamin D receptorVEGF. See Vascular endothelial growth

factor

Index 333

Very low density lipoprotein (VLDL), 173–174, 202f–203f

Very-long-chain fatty acids (VLCFAs), 171Vesicular stomatitis virus (VSV), 277Visceral adipose tissue (VAT), 234–235

BAT, 235chronic low-grade persistent inflamma-

tion, 238–239CLS, 236HF diet, 235–236hypoxia and HO-2, 237–238MetS, 236–237PUFA, 237

Vitamin D receptor (VDR), 291–292VLCFAs. See Very-long-chain fatty acidsVLDL. See Very low density lipoprotein

VSM cells. See Vascular smooth muscle cells

VSV. See Vesicular stomatitis virus

WWASP. See Wiskott–Aldrich Syndrome

proteinWhite adipose tissue (WAT), 166Wiskott-interacting protein

(WIP), 282Wiskott–Aldrich Syndrome protein

(WASP), 282

YYersinia pestis, 93, 95–96Yersinia spp., 93