LPS-mediated cell surface expression of CD74 promotes the proliferation of B cells in response to MIF

Macrophage migration inhibitory factor (MIF) is a chemokine-like inflammatory cytokine, which plays a pivotal role in the pathogenesis of inflammatory and cardiovascular diseases as well as cancer. We previously identified MIF as a novel B cell chemokine that promotes B cell migration through non-cognate interaction with the CXC chemokine receptor CXCR4 and CD74, the surface form of MHC class II invariant chain. In this study, we have analyzed the regulation of the MIF receptors under inflammatory conditions by investigating the impact of lipopolysaccharide (LPS), tumor necrosis factor-a (TNF-alpha) and interleukin-1 beta (IL-1 beta) on CD74 and CXCR4 expression in B lymphocytes. We found that both LPS and TNF-a stimulation of primary B cells and the human B myeloma cell line RPMI-8226 enhanced protein expression as well as mRNA levels of CD74 in a time-and dose dependent manner. By contrast, no effect on CXCR4 expression was observed. Selective inhibition of I kappa B alpha phosphorylation significantly attenuated LPS-induced expression of CD74, suggesting the contribution of NF-kappa B signaling pathways to the regulation of CD74 expression. Importantly, individual or simultaneous blockade of MIF or CD74 using specific neutralizing antibodies markedly affected B cell proliferation after LPS exposure. Taken together, our findings unveil a connection between the pro-proliferative activity of MIF/CD74 signaling in B cells and inflammation, offering novel target mechanisms in inflammatory cardiovascular or autoimmune pathogenesis.