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These results suggest that suppression of IL-33R expression in neutrophils, preventing IL-33-induced neutrophil migration, may be an important mechanism of anti-TNFalpha therapy of inflammation.

cytokines ͉ inflammation ͉ pain ͉ rheumatoid arthritis ͉ hyperalgesia I L-33 is a recently described member of the IL-1 family that includes IL-1␤ and IL-18. Like IL-1␤ and IL-18, IL-33 was found to have strong immunomodulatory functions (1). However, unlike IL-1␤ and IL-18, which mainly promote T-helper 1 (Th1)-associated responses, IL-33 predominantly induces the production of Th2 cytokines (IL-5 and IL-13) and increases the levels of serum Ig. IL-33 was recently found to be the ligand for the orphan receptor ST2 (1), which also is known as T1, DER4, or Fit (2-5). The interaction between IL-33 and ST2 was sufficient to trigger the activation of NF-B and all three MAPKs (p38, ERK1/2, and JNK1/2) in a mast cell line. In vitro, IL-33 enhanced IL-5 and IL-13 production by polarized Th2, but not Th1, cell lines. In addition, the administration of human IL-33 into naïve mice provoked innate type 2 cytokine, IgE production, and eosinophilia (1).The ST2 gene encodes two isoforms of ST2 protein: ST2L, a transmembrane form, and soluble ST2 (sST2) (6), a secreted form that can serve as a decoy receptor of IL-33 (1). ST2L is preferentially expressed on Th2, but not Th1, cells (7,8) and can profoundly suppress innate and adaptive immunity (9, 10). ST2 also is expressed on mast cells, macrophages, and fibroblasts. We have previously shown that sST2 is a potent inhibitor of collagen-induced arthritis in mice (11), suggesting that the IL-33-ST2 signaling pathway is a key mediator of rheumatoid arthritis (RA). Arthritic lesions are accompanied by movement limitation secondary to articular hyperalgesia, and there is consistent evidence that cytokines induce hypernociception (hyperalgesia and/or allodynia in experimental animals) (12-15). Therefore, we have investigated the role of IL-33 in immune inflammatory hypernociception in mice.We report here that IL-33 is a key mediator of methylated BSA (mBSA)-induced cutaneous and articular mechanical hypernociception. IL-33 mediates hypernociception via the sequential TNF␣ 3 IL-1␤ 3 IFN␥ 3 endothelin 1 (ET-1) 3 prostaglandin (PG) E 2 signaling cascade. These results therefore reveal a hitherto uncharacterized important pathway of antigen-induced hypernociception normally associated with Th1 response. Furthermore, our results suggest that IL-33 may be a potential therapeutic target for immune inflammatory hypernociception. Results IL-33Mediates Cutaneous Mechanical Hypernociception. IL-33 intraplantar (i.pl.) injection induced mechanical hypernociception in mice in a dose-and time-dependent manner (Fig. 1A). The response was significant from 0.5 h, reaching maximal response between 3 and 5 h, decreasing thereafter to a control level at 48 h. The IL-33-induced hypernociception was restricted to the ipsilateral paw at the doses used (data not shown), indicating a local effect. A 70 ng per paw dose and readout at 3 h were chosen for subsequent experiments. IL-33-induced cutaneous hypernociception was significantly inhibited by the treatment with sST2-Fc, but not by the Fc control (Fig. 1B...

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