Its Receptor is Widespread
The name IL-17 has been assigned to a T-cell-produced protein that acts on receptors expressed by a wide variety of cells.1,2 The sequence first was identified as CTLA8 from a murine cDNA sequence obtained by subtractive hybridization of activated T-cells.3 CTLA8 was 57% homologous with open reading frame 13 of Herpesvirus saimiri (HVS13),4 a lymphotropic virus. Neither IL-17 nor its receptor, IL-17R, has sequence similarity with known cytokines or cytokine receptors.
IL-17 was shown to activate transcription factor NF-kappa B and to induce expression of IL-6, IL-8 and surface ICAM-1 by fibroblasts and to enhance proliferation of T-cells induced by a sub-optimal costimulus, phytohemagglutinin (PHA).2 Soluble IL-17R blocked these activities. Similarly, soluble IL-17R inhibited T-cell proliferation and IL-2 production induced by conA, PHA, or anti- T-cell receptor antibody, suggesting a key role for endogenously produced IL-17 in T-cell activation. IL-17 production by human peripheral blood T-cells was largely, but not entirely, by CD4+ cells.
Yao and colleagues expressed murine IL-17 (mIL-17 or CTLA8) and the HVS homolog, HVS13, in transfected cells.2 Murine IL-17 had masses of 17 and 21 kDa, while HVS13 had masses of 17, 20, 23, and 26 kDa. Treatment of the transfectants with tunicamycin led to expression of only the 17 kDa forms, suggesting that the larger forms are N-glycosylated, consistent with glycosylation at the single site on mIL-17 and at the three potential sites on HVS13.
A partial sequence of human IL-171 (hIL-17) was obtained by amplification of genomic DNA with degenerate primers from HVS and mIL-17 sequences. This partial sequence was used to screen a T-cell clone lambda-gt10 library, leading to a sequence for a 155-amino-acid protein (predicted mass = 17.5 kDa) with 63% and 72% identity to mIL-17 and HVS13. Expression led to proteins of 15 and 20 kDa; the 20 kDa protein was eliminated by tunicamycin. Under non-reducing conditions, the expressed proteins had masses of 30 and 38 kDa, suggesting disulfide-linked dimers.
The murine IL-17 receptor (mIL-17R) was identified2 by searching for proteins that bound to an HVS13-Fc fusion protein. A cDNA expression system was screened for binding proteins, leading to two isolates that bound HVS13 or mIL-17. The open reading frame of these clones encoded an 864 amino-acid, type I transmembrane protein. This IL-17R had no homology with known sequences.
Northern analysis of RNA from various cell lines revealed expression of IL-17 mRNA primarily in a CD4+ T-cell clone and in stimulated peri-pheral blood T-cells. No expression was detected in B-cells, unstimulated T-cells or in a dozen or so other tissues. In contrast, Northern analysis with a probe to IL-17R showed expression in virtually all cells and tissues tested.
The preliminary picture that can be deduced is that IL-17 is produced by activated T-cells, activates T-cells and acts on many other cells and tissues, apparently in a proinflammatory way.
- Yao, Z. et al. J. Immunol. (1995) 155:5483.
- Yao, Z. et al. Immunity (1995) 3:811.
- Rouvier, E. et al. (1993) 150:5445.
- Albrecht, J-C. et al. (1992) J. Virol. 66:5047.