Abstract
The production and function of cytokines are highly regulated. One mechanism is the balance between pro- and anti-inflammatory cytokines. As interleukin (IL)-17A and IL-25 share the IL-17RA receptor chain, we hypothesize that IL-25 acts as an IL-17A receptor antagonist and limits its pro-inflammatory effects. The production and expression kinetics of IL-25 and its receptor chains IL-17RA and RB were analyzed in rheumatoid synoviocytes alone or in coculture with peripheral blood mononuclear cells (PBMCs). The effects of autocrine or exogenous IL-25 on synoviocytes were investigated in the presence or not of an anti-IL-25 antibody. To study the regulatory effects of IL-25, synoviocytes and/or PBMCs were exposed to IL-25 before being treated with IL-17A and tumor necrosis factor alpha (TNF-α) alone or combined. IL-25, IL-6, and bioactive IL-17A were quantified in rheumatoid arthritis (RA) patient plasma. Synoviocytes expressed and secreted IL-25, and expressed the two chains of its receptor IL-17RA and IL-17RB. IL-17RB expression was increased by TNF-α. IL-25 production occurred at a delayed time point (5 days) after stimulation with IL-17A and TNF-α. Synoviocytes pretreated with IL-25 were less responsive to IL-17A and TNF-α. PBMCs exposed to IL-25 showed a decreased production of pro-inflammatory mediators, including IL-17A with a 57% decrease; p = 0.002. IL-25 levels were elevated in the plasma of RA patients compared to healthy subjects (p = 0.03). However, these levels are not high enough to inhibit the function of circulating IL-17A. In conclusion, it was shown for the first time that synoviocytes produce IL-25, specifically at late time points and that IL-25 acts as a regulator of IL-17A-driven inflammation, as indicated by in vitro results and in vivo, in a long-term RA patient follow-up. These results may be important when considering IL-17A inhibition.
Highlights
The expression and function of cytokines are highly regulated through a large variety of mechanisms
The IL-25 expression and production were analyzed over time in rheumatoid arthritis (RA) synoviocytes treated or not with IL-17A and tumor necrosis factor alpha (TNF-α)
Our observation indicated that IL-25 was easy to detect using Enzyme-Linked Immunosorbent Assay (ELISA) with levels ranging from hundreds to thousands picograms per milliliter, as opposed to IL-17A which is present at low levels by ELISA in the serum/plasma of RA patients
Summary
The expression and function of cytokines are highly regulated through a large variety of mechanisms. Interleukin-17A is the prototype cytokine of the IL-17 family, which consists of six members, from IL-17A to IL-17F. IL-17A and IL-17F share 50% sequence homology and are involved in chronic inflammation and autoimmunity [2, 3]. IL-25 ( known as IL-17E) shares only 17% sequence homology with IL-17A. Unlike other members of the family, it is involved in the regulation of type-2 immune response, including host defense against parasites [4] and allergy [5, 6]. IL-25 regulates inflammation by controlling the Th17 response [7,8,9,10]
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