SummaryAnalysis of the cDNA encoding murine interleukin (IL) 17 (cytotoxic T lymphocyte associated antigen 8) predicted a secreted protein sharing 57% amino acid identity with the protein predicted from ORF13, an open reading frame ofHerpesvirus saimiri. Here we report on the cloning of human , the human counterpart ofmurine IL-17. hlL-17 is a glycoprotein of 155 amino acids secreted as an homodimer by activated memory CD4 + T cells. Although devoid of direct effects on cells of hematopoietic origin, hlL-17 and the product of its viral counterpart, Olq.F13, stimulate epithelial, endothelial, and fibroblastic cells to secrete cytokines such as IL-6, IL-8, and granulocyte--colony-stimulating factor, as well as prostaglandin E2. Furthermore, when cultured in the presence of hlL-17, fibroblasts could sustain the proliferation of CD34 + hematopoietic progenitors and their preferential maturation into neutrophils. These observations suggest that hlL-17 may constitute (a) an early initiator of the T cell-dependent inflammatory reaction; and (b) an element of the cytokine network that bridges the immune system to hematopoiesis.T lymphocytes produce an array of small proteins that are involved in cell growth, inflammation, immunity, differentiation, and repair. These protein mediators referred to as cytokines are not produced constitutively by T cells, but rather are induced after receptor-mediated T cell activation (1, 2). Murine cytotoxic T lymphocyte associated antigen-8 (mCTLA8) 1, a cDNA previously cloned by lq.ouvier et al. (3) from a T cell subtraction library, displays some of the features ofa cytokine gene: in particular, a pre1Abbreviations used in this paper: hlL-17, human IL-17; HVS, Herpesvirus saimiri; ORF13, open reading frame 13; mCTLA8, murine cytotoxic T lymphocyte-associated antigen 8; PGE 2, prostaglandin E2; PI, PMA and ionomycin.Parts of this work were presented at

Objective. To investigate the presence and role of interleukin-17 (IL-17) in rheumatoid arthritis (RA), and its regulation by antiinflammatory cytokines.Methods. The production of IL-17 was measured in supernatants of RA, osteoarthritis (OA), and normal synovial tissue pieces cultured ex vivo. Quantification of IL-17 was performed using a specific biologic assay. IL-17 gene expression was investigated by reverse transcriptase-polymerase chain reaction (RT-PCR)-techniques. Immunohistochemistry was used to evaluate the frequency of IL-17-positive cells in synovium.The secretion of IL-17 by synovium was measured in the presence of IL-4, IL-13, and IL-10. In addition, the contributions of exogenous and endogenous IL-17 to IL-6 production by RA synovium were studied.Results. Functional IL-17 was spontaneously produced by 16 of 18 RA (mean ؎ SEM 41.7 ؎ 11.4 units/ml), 2 of 12 OA (5.3 ؎ 4.5 units/ml), and 0 of 3 normal synovial explant cultures. IL-17 messenger RNA expression was demonstrated by RT-PCR in 4 of 5 RA and 0 of 3 OA synovial samples. By immunostaining of RA synovium, IL-17-producing cells were found in the T cell-rich area. Addition of both IL-4 and IL-13 completely inhibited the production of IL-17, whereas IL-10 had no effect. Addition of exogenous IL-17 to RA synovium resulted in an increase in IL-6 production, whereas that of a blocking anti-IL-17 antibody reduced production of IL-6.Conclusion. The T cell cytokine IL-17 was found to be highly produced by RA, but not by OA, synovium. Its production and function were down-regulated by IL-4 and IL-13. These results indicate that IL-17 contributes to the active, proinflammatory pattern that is characteristic of RA. Through the contribution of IL-17, some Th1-like T cells appear to mediate synovial inflammation.

T helper (Th)17 cells producing interleukin (IL)-17 play a role in autoimmune and allergic inflammation. Here, we show that IL-23 induces IL-17 in the lung and IL-17 is required during antigen sensitization to develop allergic asthma, as shown in IL-17R–deficient mice. Since IL-17 expression increased further upon antigen challenge, we addressed its function in the effector phase. Most strikingly, neutralization of IL-17 augmented the allergic response in sensitized mice. Conversely, exogenous IL-17 reduced pulmonary eosinophil recruitment and bronchial hyperreactivity, demonstrating a novel regulatory role of IL-17. Mechanistically, IL-17 down modulated eosinophil-chemokine eotaxin (CCL11) and thymus- and activation-regulated chemokine/CCL17 (TARC) in lungs in vivo and ex vivo upon antigen restimulation. In vitro, IL-17 reduced TARC production in dendritic cells (DCs)—the major source of TARC—and antigen uptake by DCs and IL-5 and IL-13 production in regional lymph nodes. Furthermore, IL-17 is regulated in an IL-4–dependent manner since mice deficient for IL-4Rα signaling showed a marked increase in IL-17 concentration with inhibited eosinophil recruitment. Therefore, endogenous IL-17 is controlled by IL-4 and has a dual role. Although it is essential during antigen sensitization to establish allergic asthma, in sensitized mice IL-17 attenuates the allergic response by inhibiting DCs and chemokine synthesis.

IntroductionInterleukin-17 (IL-17), originally identified by Rouvier et al 1 as cytolytic T-lymphocyte (CTL)-associated antigen 8, is a T-cellderived cytokine with homology to Herpesvirus saimiri. [1][2] It is expressed mainly by activated CD4 ϩ CD45RO ϩ memory T cells. [3][4] CD4 T cells can be classified into T-helper (Th) 1 cells, which secrete interferon (IFN) ␥, IL-2, and tumor necrosis factor (TNF) ␤; Th2 cells, which produce IL-4, IL-5, IL-6, IL-10, and IL-13; and Th0 cells, a common precursor with the ability to release both IFN␥ and IL-4. Thirty percent of Th0/Th1 clones have been shown to produce IL-17, whereas Th2 clones never express IL-17. 5 IL-2 and IL-15 were found to increase IL-17 production by human peripheral blood (PB) mononuclear cells. 6 IL-17 is considered to be a proinflammatory cytokine because it increases IL-6 and IL-8 production by macrophages, fibroblasts, keratinocytes, and synovial cells 2,3,[7][8][9] and nitric oxide production by human osteoarthritic cartilage. 10,11 IL-17 also induces secretion of IL-1␤ and TNF-␣ by human macrophages and endothelial cells. 7,12 IL-17 activates the nuclear factor B and activator protein 1 transcription factors, which may explain its proinflammatory properties. 10,13 In addition, IL-17 induces production of granulocyte colony-stimulating factor and CXC chemokines that stimulate granulopoiesis and recruitment of neutrophils into tissues. [14][15][16] The IL-17 receptor is a type I transmembrane protein that is expressed in virtually all cells and tissues, in contrast to the restricted expression of IL-17, which is confined to T cells. 2,17 This receptor has no sequence similarity with any other known cytokine receptor. It interacts with the adapter molecule TNF receptorassociated factor 6, which is required for IL-17 signaling. 18 The exact role of IL-17 in disease is unknown. IL-17 has been found to promote cartilage destruction in various forms of arthritis. 19,20 Overproduction of IL-17 has been observed in the synovium of patients with rheumatoid arthritis 21 and in PB lymphocytes from patients with systemic sclerosis. 22 In a previous study, we found that IL-17 promotes tumorigenicity of human cervical tumors in nude mice. 23 Because this paradoxical tumor-promoting activity of IL-17 in the absence of T cells was unexpected, we conducted the current study to analyze the effect of IL-17 on the growth of syngeneic tumors in immunocompetent mice. We found that IL-17 inhibits the growth of 2 hematopoietic tumors, mastocytoma P815 and plasmocytoma Materials and methods Mice and tumor cell linesFemale Balb/c, DBA/2, and athymic nude/nude mice 6 to 8 weeks of age (Iffa Credo L'Arbresle, France) were used in this study. The mouse plasmocytoma J558L and mastocytoma P815 cell lines were obtained from the American Type Culture Collection (Manassas, VA). The mouse squamous cell carcinoma KLN 205 was purchased from the European Collection of Cell Culture (Salisbury, Wiltshire, United Kingdom). The cell lines were cultured in RPMI supplemented with 10% fet...