INTERLEUKIN-17

IL-17 sequence was first isolated as the murine Cytotoxic T Lymphocyte Antigen 8 (CTLA-8) from a substracted cDNA library of a PMA+ionomycin activated hybridoma resulting from the fusion of mouse cytotoxic T cells with a rat T lymphoma cell line [1]. The CTLA-8 sequence presented several features of a cytokine gene: eight AU-rich repeats in the 3′ untranslated region, an open reading frame encoding a putative secreted protein of 150 aa, a 57% homology with the putative protein encoded by the ORF13 gene of herpes virus Saimiri, a T lymphotropic virus well known for its ability to transform

human T cells. Evidence for the capture of CTLA-8 sequence by a virus further supported the hypothesis that this molecule could play some role in the immune response [2]. Meanwhile, two groups [3,4] found a sequence very close to the CTLA-8 sequence in mouse thymocytes cDNA libraries, demonstrating that the initial sequence was derived from the rat lymphoma. Using the rat sequence, two groups independently cloned the human counterpart gene [5,6] and caracterized partially the biological activity of this novel T cell-secreted molecule which was proposed by Yao [4] for the designation of interleukin 17. Indeed, recombinant IL-17 was shown to be a homodimeric soluble molecule of about 32 Kd secreted only by activated human memory T cells [5,6], circulating and spleen T cells or mouse αβTCR+CD4-CD8-thymocytes [3] which induced the secretion of other cytokines (including IL-6, IL-8, and G-CSF) by stromal cells. This warranted the novel protein its final designation as interleukin 17 (IL-17). IL17 was also able to induce ICAM-1 surface expression by fibroblasts [6], to enhance T cells proliferation (at least in mouse) [4], and to indirectly support both the growth and differentiation of CD34+ human progenitors into neutrophils when cocultured in presence of irradiated fibroblasts [5]. The mouse and human IL-17 recep-tors were recently cloned, which appear to be ubiquitously distributed [4,7]. IL-17R displays an unusually long intracellular domain, but can not be included into existing families of cytokine receptors. In vivo experiments with mouse have shown that injection of IL-17 induces an acute neutrophilia and protection against E. coli infection (Krishna et al., submitted paper). Moreover, preliminary data with kidney graft rejection samples and rheumatoid arthritis synovium support the hypothesis that IL-17 may play an upstream role in T celldependent inflammatory responses [8,9]. The molecular aspects of IL-17 and of its receptor, their expression patterns, as well as the early in vivo biological studies are reviewed.