Role of a new truncated CD74 isoform in increased IL-17 secretion from stromal-immune cell interactions.

INTRODUCTION: Stromal-immune cell interactions promote pro-inflammatory cytokine secretion such as IL-17. IL-17 is involved in several chronic inflammatory diseases, affecting joints and skin. Podoplanin has been already identified as partially involved in high IL-17 secretion resulting from these cell interactions. METHODS: The aim of this study was to identify new molecules, using co-cultures of activated peripheral blood mononuclear cells and synoviocytes (5:1 ratio). Cell interactions were critical to induce a high IL-17 production. The blockade of podoplanin inhibited this production, approximately 40%, confirming the contribution of other molecules. A battery of mouse monoclonal anti-human RA synoviocyte antibodies were tested in co-cultures and several were selected for their inhibitory effect on IL-17. RESULTS: Cloning by expression allowed identifying the target of the selected 8350 antibody, a truncated isoform of CD74. CD74 blockade in co-cultures by 8350 antibody and a commercial antibody inhibited IL-17 production by 40%, but 8350 antibody had a limited effect on IL-10 inhibition. Furthermore, cell interactions increased CD74 expression, at mRNA and protein levels. CONCLUSION: This study identified truncated CD74 isoform as a novel molecule directly involved in high IL-17 secretion resulting from cell interactions. Inhibition of this truncated CD74 could represent a new therapeutic option for diseases with IL-17 involvement.