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Joint Bone Spine 75 (2008) 517e519

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Editorial

Interleukin 23: A key cytokine in chronic inflammatory disease

Keywords: IL-23; Inflammation; Psoriasis; Inflammatory bowel disease; Spondyloarthropathies; Rheumatoid arthritis

Progress in the understanding of immunological eventsinvolved in the inflammatory process, most notably those drivenby cytokines, has shed new light on the pathophysiology ofinflammatory disease, thereby suggesting targets for treatment.The effectiveness of drugs that inhibit TNFa, IL-1, or IL-6establishes the validity of designing treatments that targetspecific pathophysiological mechanisms. IL-23 is generatingconsiderable interest as a key participant in the central regula-tion of the cellular mechanisms involved in inflammation and,therefore, as a potentially valuable treatment target.

1. The cytokine IL-23

IL-23 is a heterodimeric cytokine composed of two subunits,a p40 subunit also found in IL-12 and a specific p19 subunit(also known as the IL-23 alpha subunit) [1,2]. Most of thereagents used to assay IL-12 detect the p40 component sharedwith IL-23. Therefore, a number of effects heretofore ascribedto IL-12 may in fact be mediated by IL-23. The IL-23 receptoris also a heterodimer. It consists of a subunit shared with the IL-12 receptor (IL-12Rb1) and of the IL-23R subunit [1].

IL-6 and TGF-b induce the expression of the IL-23Rreceptor on Th17 cells [2]. IL-23 can then stimulate na€ıveCD4þ T cells to differentiate into Th17 cells, which produceIL-17, a proinflammatory cytokine that stimulates theproduction of molecules such as IL-1, IL-6, TNFa, NOS-2,and chemokines responsible for inflammation [3,4] (Fig. 1).

IL-23 is produced by dendritic cells, macrophages [3],other antigen-presenting cells, and keratinocytes [1]. IL-23production is stimulated by a number of microorganisms(Gram-positive and Gram-negative bacteria, lipopolysaccha-rides) [3] and by the activation of receptors involved in innateimmunity, including toll-like receptor-4 (TLR 4) [1]. IL-23R isexpressed by active dendritic cells and by macrophages, andIL-23 can stimulate macrophages to produce proinflammatorycytokines. These facts suggest that IL-23 may induce an

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autocrine loop within the innate immune system, leading tothe production of numerous mediators of inflammation [2].

2. IL-23 and animal models

Knock-out mice for p40 or p19, or for one of the IL-23 receptorsubunits (IL-23R or IL-12Rb1), develop less severe symptoms ofmultiple sclerosis, inflammatory bowel disease, or collagen-induced arthritis, compared to intact mice [5]. Transgenic micethat overexpress each of the IL-23 subunits spontaneouslydevelop inflammatory diseases. Ubiquitous expression of p19leads to severe systemic inflammation, with high circulatinglevels of TNFa and IL-1 and early death [1]. Overexpression ofp40 by keratinocytes is responsible for an inflammatory skindisease [1]. In the collagen-induced arthritis mouse model,absence of IL-23 p19 protects against arthritis, whereas absenceof IL-12 leads to exacerbated arthritis, suggesting that IL-23 maybe a key promoter of autoimmune joint inflammation [6].

3. IL-23 and inflammatory disease

IL-23 and IL-17 are found in psoriatic lesions, possibly asa result of stimulation by bacteria [3]. Compared to normalskin, psoriatic lesions contain high levels of IL-23 andincreased amounts of messenger RNAs for p19 and p40 [1].The p19 and p40 proteins are expressed in the dendritic cellsof the dermis and the keratinocytes of psoriatic lesions, andIL-23 production correlates with disease severity [1].

Bacteria-induced IL-23 expression has been documented indendritic cells of the lamina propria of the terminal ileum [3].

IL-17 and IL-23 p19 are usually detectable in serum, jointfluid, and synovial biopsies from patients with rheumatoidarthritis (RA) but are absent in patients with osteoarthritis [5].In RA, IL-23 p19 levels correlate with IL-17 levels in theserum and joint fluid and with TNFa levels in the serum;furthermore, synovial IL-23 p19 levels are higher in patientswith erosions [7]. We showed that serum IL-17 levels (which

.

NaiveT cell

Th17

Th1

Th2

Treg

IL23R IL 12B1

IL-4

IL-12IL-23

IL-6

TGF-β

IL-17

IL-6

TNF-α

IFN-γ

IL-2

TNF-α

IL-4

IL-10

DCDC

Fig. 1. Role for cytokines in T-cell differentiation (from Refs. [1e4]). DC, dendritic cell; and Treg, regulatory T cell.

518 Editorial / Joint Bone Spine 75 (2008) 517e519

reflect IL-23 activity) are higher in patients with ankylosingspondylitis than in controls [8]. The messenger RNAs for IL-23 p19 and p40 are overexpressed in temporal artery biopsiesfrom patients with giant cell arteritis, compared to controls [9].

Thus, converging lines of evidence indicate a role for IL-23in chronic inflammatory diseases characterized by jointmanifestations.

4. Genetic polymorphism of the IL-23 receptor andinflammatory disease

Specific polymorphisms of the IL-23R gene are associatedwith chronic inflammatory disease. The Arg381Gln variant ofthe IL-23R gene confers strong protection against Crohn’sdisease [10]. Associations linking specific IL-23R mutations toCrohn’s disease and, to a lesser extent, to ulcerative colitis,were subsequently confirmed in other studies [11]. The sameArg381Gln variant protects against cutaneous psoriasis [12].The amino acid at 381 is located within the JAK-2 bindingdomain of IL-23. Variations at this site may interfere with thesignaling cascade induced by binding of IL-23 to the IL-23R,thereby preventing the activation of Th17 and protectingagainst disease [1].

Among loci recently shown to be associated with anky-losing spondylitis, one includes the IL-23R gene [13]. TheArg381Gln variant protects against ankylosing spondylitis[14,15] and psoriatic arthritis [16]. Finally, functional variantsof the IL-23R gene are associated with RA [17].

5. Effects of treatments on the IL-23 axis

In mice with experimental colitis, TNFa blockade signifi-cantly decreased the expression of IL-23 p19 and IL-17 TNF

in the colon, while concomitantly improving the mucosalinflammation [18]. Etanercept therapy in patients with RAsignificantly decreased the levels of IL-23, which correlatedwith the DAS 28 [19].

6. Treatments targeting IL-23

In male DBA1 mice, collagen-induced arthritis is associ-ated with increased expression levels of IL-23 and IL-23R bythe synovial membrane. Intraarticular injection of an antibodyto IL-23R significantly improved the arthritis and decreasedthe synovial expression of IL-23, IL-23R, IL-17, IL-1, IL-6,and TNFa [20].

IL-23 can be blocked by a human monoclonal recombinantantibody against IL-12/23 p40 (CNTO-1275 or ustekinumab).This antibody was investigated in a randomized placeboe-controlled trial in patients with Crohn’s disease [21]. With thehigher dose, the clinical response rate was 75%, compared to25% with the placebo, and the remission rate was 50%. Theclinical improvements were accompanied with decreases inthe secretion of IL-12, interferon gamma, and TNFa bymononuclear cells in the colonic lamina propria [21]. A phase2 study was conducted to evaluate the anti-IL-12/23 antibodyin patients with psoriasis. After 12 weeks, the clinical effectswere significantly greater with the antibody, in all dosages,than with the placebo. The adverse-event rate was not signif-icantly different between the antibody groups and the placebogroup [22].

The anti-IL-12/23 antibody was assessed in patients withpsoriatic arthritis in a randomized placeboecontrolled double-blind trial [23]. After 12 weeks, ACR20, ACR50, and ACR70response rates were higher in the treatment group (42%, 25%,and 10%) than in the placebo group (14%, 7%, and 0%). The

519Editorial / Joint Bone Spine 75 (2008) 517e519

beneficial effects on the joint disease lasted until week 36 inthree-quarters of the patients. Improvement in the skin lesionswere noted. The treatment seemed well tolerated.

The IL-12/23 axis can be blocked by using other mono-clonal antibodies (ABT-874) or molecules that prevent thetranscription of IL-12/23 (STA 5326), which are being eval-uated [24]. Furthermore, IL-23 can be targeted downstreamfrom the TNFa activation pathways, for instance by inhibitingIL-17.

In sum, the IL-23 axis, which is stimulated by infectionsand other events, is responsible for Th17 differentiation andplays a role in the pathophysiology of inflammation, mostnotably in patients with spondyloarthropathies. IL-23 can betargeted by administering an antibody against IL-23 p12/23,which is being developed. It would be useful to designdrugs that specifically target the p19 IL-23 subunit or the IL-_23R, thus inhibiting IL-23 without modifying the effects ofIL-12.

A considerable body of concordant evidence availablenow suggests that IL-23 may orchestrate the pathogenesis ofchronic inflammatory diseases, including those affecting thejoints.

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Daniel WendlingService de Rhumatologie, CHU Minjoz et,

EA 3186 (Agents Pathogenes et Inflammation),Universite de Franche-Comte, 25030 Besancon, France

E-mail address: dwendling@chu-besancon.fr

7 March 2008

Available online 24 September 2008