IL-17 had started its life under the name of CTLA-8, a gene product without clear function. At the time of IL-17’s discovery, I was encouraging the Schering-Plough facility near Lyon to use IL-4 to control RA inflammation. The Schering-Plough group was very active in the field of B cells, and the new molecule called CTLA-8 was tested in all the B-cell and T-cell assays in routine use in the laboratory. No effect was observed and the project was going to be dropped until someone suggested testing an effect of RA synoviocytes, which I had available in my laboratory.
This last effort to find a function for IL-17 was successful; induction of IL-6 by synoviocytes was observed, making IL-17 indeed a French discovery. At the same time as I was conducting this work, researchers at Immunex in Seattle (now part of Amgen) reached a similar conclusion from their work on the IL-17 receptor.7 At this early stage of research, inhibitors were obtained—including a mouse anti-human IL-17 monoclonal antibody and an anti-mouse IL-17 soluble receptor also active on human IL-17—so these tools could have been transferred quickly to the clinic as early as 1996.
The link between IL-17 and RA was further extended when we showed that pieces of RA synovium could produce bioactive IL-17. This activity was measured with a bioassay where supernatants from pieces of cultured RA synovium induced a massive production of IL-6 by RA synoviocytes.8 Using the first available monoclonal antibody to block human IL-17, such production was reduced by two-thirds. This robust production of IL-6 using supernatants with IL-17 contrasted with the limited effect of recombinant IL-17 alone.
The conclusion of these experiments was that bioactive IL-17, produced by the RA synovium, interacted with other known stimulating cytokines, such as TNF and IL-1, to induce IL-6 production (See Figure 1, right). These interactions were shown to be the consequence of synergy. We know now that IL-17 increases the effects of TNF and IL-1 by increasing the mRNA half-life of genes induced by these cytokines. Observation of synergistic interactions in mesenchymal cells supports the regulatory nature of signals from T cells acting on monocytes and dendritic cells.
The inhibitory effect of IFNγ on IL-17 production and function as clarified in 2003 by Masanori Kawashima, who was working in my laboratory.9 Dr. Kawashima was comparing the effect of IL-12, with or without IL-18, on the expression of IFNγ and IL-17. In the paper published on these experiments, we wrote, “Results for healthy PBMC and RA synovium cells show a discrepancy between IFNγ and IL-17 regulation by IL-12 and IL-18. In particular, IL-12 plus IL-18 synergistically increased the expression of IFNγ mRNA, but decreased that of IL-17, in both PBMC and RA synovium cells.” We concluded that IFNγ had a critical role for inflammation and IL-17 a critical role for destruction.
