Charles J Malemud
Case Western Reserve University, USA
Title: Interleukin-6-mediated signal transduction in autoimmune disorders
Biography
Biography: Charles J Malemud
Abstract
Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines found at elevated levels in various autoimmune disorders such as rheumatoid arthritis (RA). In that regard, IL-6 was shown to play a prominent role in the pathogenesis and progression of RA. However, in order to establish how IL-6 could be involved in the progression of RA through its capacity to alter the function(s) of articular chondrocytes, we explored several relevant mechanisms by which IL-6 affected human chondrocytes in vitro. We found that incubating the C28/I2 line of immortalized human chondrocytes with recombinant human IL-6 (rhIL-6), the IL-6-like cytokine, rh-oncostatin M or the adipokine, rh-adiponectin caused phosphorylation (i.e. activation) of ERK1/2, p38α MAPK and JNK1/2. We also reported that rhIL-6 activated STAT-1, STAT-3 and STAT-5 without altering total STAT-1, -3 and -5, although STAT-1 was constitutively phosphorylated in another human chondrocyte line, T/C28a2. Matrix metalloproteinase-9 (MMP-9) plays a key role in RA by degrading cartilage extracellular matrix proteins. We found that rhIL-6 increased the synthesis of MMP-9 in the human chondrocyte lines. Of note, production of MMP-9 was inhibited by tocilizumab, a fully humanized monoclonal antibody which neutralizes the interaction of IL-6 with the membrane-bound IL-6 receptor-α/gp130 complex, membrane IL-6R or soluble IL-6 receptor (sIL-6R). Whereas the combination of rhIL-6 and sIL-6R significantly increased MMP-9 compared to sIL-6R, sIL-6R alone inhibited MMP-9 production by C28/I2 chondrocytes when compared to rhIL-6. This latter finding may be germane in the design of a future biological therapy for RA.