BiP, an anti-inflammatory ER protein,is a potential new therapy for the treatment of rheumatoid arthritis

摘要

The endoplasmic reticulum chaperone and stress protein BiP has hitherto beenconsidered as having only crucial intracellular cell protective functions. However, wehave shown that BiP can be present in the extracellular environment and that it bindsto a putative but as yet uncloned cell surface receptor. It will stimulate human monocytesvia this receptor to express a gene profile that is anti-inflammatory. It will generate Tcells with a regulatory function from human peripheral blood most likely by alteringdendritic cell development. Intravenous BiP will both prevent and treat ongoing collageninduced arthritis in the DBA/1 mouse. Part of the suppression of arthritis is linked tointerleukin (IL)4 as BiP-specific lymph node and spleen cells from these mice secreteIL4, and BiP has no suppressive effect on collagen induced arthritis in IL4 knockoutmice. Lymph node and spleen cells isolated from mice administered intravenous BiP willsuppress arthritis when transferred intravenously into recipient arthritic mice withoutany further BiP having to be given. Thus, both in vitro work with human peripheral bloodmononuclear cells and in vivo work in the collagen arthritis model lead to the conclusionthat BiP induces regulatory cells. Finally, intravenous BiP will ablate the inflammatorycell infiltrate and inflammatory cytokine expression in rheumatoid synovial membranetissue transplanted subcutaneously into SCID mice. The conclusion from all this experi-mental work is that BiP may be a novel therapy for the treatment of patients with rheu-matoid arthritis.