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...

Quercetin (1) is known to have both antioxidant and antinociceptive effects. However, the mechanism involved in its antinociceptive effect is not fully elucidated. Cytokines and reactive oxygen species have been implicated in the cascade of events resulting in inflammatory pain. Therefore, we evaluated the antinociceptive mechanism of 1 focusing on the role of cytokines and oxidative stress. Intraperitoneal and oral treatments with 1 dose-dependently inhibited inflammatory nociception induced by acetic acid and phenyl-p-benzoquinone and also the second phase of formalin- and carrageenin-induced mechanical hypernociception. Compound 1 also inhibited the hypernociception induced by cytokines (e.g., TNFalpha and CXCL1), but not by inflammatory mediators that directly sensitize the nociceptor such as PGE2 and dopamine. On the other hand, 1 reduced carrageenin-induced IL-1beta production as well as carrageenin-induced decrease of reduced glutathione (GSH) levels. These results suggest that 1 exerts its analgesic effect by inhibiting pro-nociceptive cytokine production and the oxidative imbalance mediation of inflammatory pain.

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Background and purpose: Atorvastatin is an inhibitor of the enzyme 3-hydroxyl-3-methylglutaryl coenzyme A reductase used to prevent coronary heart disease. We have studied the analgesic effect of atorvastatin in inflammatory models in which a sequential release of mediators (bradykinin, (BK), tumour necrosis factor-a (TNF-a), interleukin-1b (IL-1b) and the chemokine, KC/CXCL) links the stimulus with release of directly acting hypernociceptive mediators such as prostaglandin E 2 (PGE 2 ). Experimental approach: The effects of orally administered atorvastatin on inflammatory mechanical hypernociception in mouse paws were evaluated with an electronic pressure-meter. Cytokines and PGE 2 were measured by ELISA and RIA. Key results: Treatment with atorvastatin for 3 days dose-dependently reduced hypernociception induced by lipopolysaccharide (LPS) or that following antigen challenge in sensitized animals. Atorvastatin pre-treatment reduced hypernociception induced by bradykinin and cytokines (TNF-a, IL-1b and KC), and the release of IL-1b and PGE 2 in paw skin, induced by lipopolysaccharide. The antinociceptive effect of atorvastatin on LPS-induced hypernociception was prevented by mevalonate co-treatment without affecting serum cholesterol levels. Hypernociception induced by PGE 2 was inhibited by atorvastatin, suggesting intracellular antinociceptive mechanisms for atorvastatin. The antinociceptive effect of atorvastatin upon LPS-or PGE 2 -induced hypernociception was prevented by non-selective inhibitors of nitric oxide synthase (NOS) but not by selective inhibition of inducible NOS or in mice lacking this enzyme. Conclusions and implications: Antinociceptive effects of atorvastatin depend on inhibition of cytokines and prostanoid production and on stimulation of NO production by constitutive NOS. Our study suggests that statins may constitute a novel class of analgesic drugs.