Role of Cytokines as Inflammatory Mediators, Endocrine

7/30/2019 Role of Cytokines as Inflammatory Mediators, Endocrine

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Role of cytokines as inflammatorymediators, endocrine & immune

response to injury

Dr. Amitabha Das

PGT

Dept. of General Surgery


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Inflammation

An extremely complex process

Involves numerous factors and cell types

Manifested by-1. color

2. rubor

3. dolor

4. tumor

5. functio laesa


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Mediators of inflammation

Chemical mediators:

Endogenous- pro & anti-inflammatory.

Exogenous.

Cells

Neural factors

Hormonal factors


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Cytokines

Most important endogenous mediators.

Acts by paracrine, autocrine and

endocrine fashion. Shows pleotropism and redundancy.

Structurally 2 types: I (eg, IL-2,3) & II (eg, IFN

& IL-10). Funtionally 2 types: TH1 or pro-inflammatory

(eg, IFN)and TH2 or anti-inflammatory (eg,

IL-4).


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Interferons

Key component of innate immunity.

3 types- alpha (a), beta (b), gamma (y). Gamma subtype is pro-inflammatory.

Gamma is produced by CD4+TH1,

CD8+TH1 & NK cells. IL12 & 18 stimulate production.

Acts via JAK-STAT pathway.


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Tumour necrosis factor

Most important pro-inflammatory mediator.

Also called cachectin or TNF-a.

Belongs to a large family of related groupof ligands- LT-a or TNF-b, FAS-L,CD40L,RANKL & TRAIL.

Most of these ligands involved in cellproliferation and apoptosis except TNF-a.

Secreted by monocyte/ macrophages, T &

B cells, mast cells etc.


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List of Stimuli Known to Initiate

Release of Tumor Necrosis Factor

Endogenous factors:

Cytokines (TNF-, IL-1, IFN-, GM-CSF,IL-2), Platelet-activating factor, Myelin P2

protein, HMGB1, HSP70, HSP60.

MicrobeDerivedFactors:

Lipopolysaccharide, Zymosan,

Peptidoglycan, Streptococcal pyrogenicexotoxin A, Streptolysin O, Lipoteichoicacid, Staphylococcal enterotoxin B,Staphylococcal toxic shock syndrome toxin-1, Lipoarabinomannan, Bacterial DNA, Flagellin.


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Tumour necrosis factor

Activates coagulation cascade along withIL-1.

Acts by activation of NF-kB. Acts on 2 types of receptors-TNFR1&2.

Extracellular part of TNFR shed intocirculation and forms soluble TNFR.

Gluco corticoids, pentoxifylline inhibit TNF.

Infliximab a monoclonal antibody to TNF

Etanercept, a TNF receptor blocker.


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Interleukin-1

Family of 3 protiens: IL-1a, IL-1b and IL-1receptor antagonist.

Production triggered by: LPS, TNF, GM-CSF,IL-1& other cytokines.

Synthesized in monocyte/ macrophages,

neutrophils, endothelium, lymphocytes etc. Acts on 2 types of receptors IL-1RI & II.

IL-1RII, IL-1RA and soluble IL-1R are anti

inflammatory.


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Physiologic effects of IL-1 & TNF

Fever

Headache

Anorexia

Increased plasma adrenocorticotropic hormone

Hypercortisolemia Increased plasma nitrite/nitrate levels

Systemic arterial hypotension

Neutrophilia & transient neutropenia

Increased plasma acute phase protein

Hypoferremia & hypozincemia Increased plasma level of IL-1RA, TNF-R1& 2, IL-6,8

Activation of coagulation cascades

Increased platelet count

Pulmonary edema

Hepatocellular injury


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Chemokines

These are cytokines involved intochemotaxis.

Mainly produced by macrophage andendothelial cells.

Structurally divided into 4 types:

CXC or a- chemokines(IL-8)CC or b- chemokines (MCP1)

C

CX3C


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Anti-inflammatory cytokines

These are IL-4, 10 & 13.

Produced by TH2 cells

Down regulates pro-inflammatory cytokines& cell mediated immunity.

Promotes anti-inflammatory agents like- IL-

1RA, IL-1RII, 15- lipoxygenase. Induces humoral immunity and class II MHC

molecules on b cells.


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Other cytokines

IL-6 acts both as pro & anti-inflammatorymediator.

It is a primary mediator of hepatic synthesisof acute phase reactants.

IL-11 is a potent growth factor for

thrombopoiesis. IL-12 & 18 are important stimulators of IFN

production.


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Arachidonic acid metabolites


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Funtions of AA metabolites

PGI-2 causes vasodilatation and inhibitsplatelet aggregation.

TXA-2 causes vasoconstriction and plateletaggregation.

PGD2,E2,F2a are involved in development

of edema & vasodilatation. LTs cause vasoconstriction, broncho-

constriction & increased capillarypermeability.


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Other mediators

High mobility group B1

Platelet activating factor

Nitric oxide: it enhances vasodilatation,edema formation & inhibits myocardialinotropy.

Vasoactive amines: Histamine & serotonin-causes vasodilatation & increasedpermeability.


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Contd

Plasma proteases:

a. complement system-C3a, C5a,

C567 complex.b. coagulation system- factor IIa, Xa,

XIIa.

c. kinin system- bradykinin. Lysosomal products

Neuropeptides


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Exogenous mediators

LPS: 3 subunits, stable lipid A, variableoligosaccharide & side chain.

Interacts via TLR4 & CD14.Causes profound activation of IL-1 & TNF.

Circulates in plasma with LBP.

Lipoteichoic acid Lipo-arabinomannan

zymosan


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Cellular mediators

Neutrophils: kill invading pathogens byoxidative and non-oxidative pathwaysfollowing phagocytosis. Major cellresponsible for end organ damage in SIRS.

Monocyte/ Macrophage: professionalphagocytes and antigen presenting cells.

Endothelial cells: respond to adverseenvironmental stimuli by releasingcytokines, adhesion molecules & reactive

oxygen species.


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Neurological mediators

CNS regulates inflammation via autonomic

signaling. Afferent signal reaches brain via both

circulation and neural pathways.

Hypothalamus is primary regulating site ofinflammation


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Hormonal mediators

Plays an important role

ACTH: loss of circadian rhythm seen during injury.

Insulin: injury decreases insulin release & producesinsulin resistance.

Catecholamines: major hormones regulating

hypermetabolic state following inury & prevents

leukocyte margination.

Growth hormone & insulin like growth factors.

Aldosterone


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Glucocorticoids

Known for its anti-inflammatory effects.

Supresses the pro-inflammatory cytokines

like TNF, reduces T-cell, NK- cell & neutrophilfunctions and suppresses chemotaxis andphagocytosis by mononuclear cells.

Produces hyperglycemia & insulinresistance.

Macrophage inhibitory factor is anendogenous antagonist of gluco-

corticoids.


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Clinical aspects

Inflammation

Healing Destruction

Several diseases arise due to unregulated

progression of inflammation. eg, inflammatory

bowel disease.


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SIRS

Most dreaded complication of inflammation insurgical patients.

Diagnosed by:

Sepsis, a form of SIRS with documented source ofinfection, associated with very high morbidity and

mortality.

Manifestation of 2 or more of these:temp.>38 or 90resp rate > 20 or PaCO2 < 32 mmhg

WBC >12000 or < 4000 with 10%immature cells


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Future prospects

Newer anti-inflammatory agents are beingprepared and undergoing studies.

These will play pivotal role in sepsismanagement.

They are:

monoclonal antibodiesnovel antagonists

recombinant anti-inflammatory

cytokines.


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Summary

Inflammation is a protective response toinjury seen in vertebrates.

Mediated by numerous cell types andsubstances in complex way.

While it promotes healing, imbalancebetween its mediators can be devastating.


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Conclusion

While all individuals respond to injury byproducing inflammation the ultimateoutcome varies in different individuals.


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Role of Cytokines as Inflammatory Mediators, Endocrine