Meprin metalloproteases inactivate interleukin-6 [Immunology]

January 28th, 2014 by Keiffer, T. R., Bond, J. S.

Meprins have been implicated in the pathogenesis of several inflammatory diseases including inflammatory bowel disease, in which the cytokine interleukin-6 (IL-6) is a prominent effector molecule. Because IL-6 levels are markedly elevated in meprin α and α/β knockout mice in an experimental model of IBD, the interaction between meprins and IL-6 were studied. The results demonstrate that rodent and human meprin A and B cleave IL-6 to a smaller product and subsequently are capable of extensive degradation of the cytokine. Analysis of the limited degradation product formed by meprin A indicated that 3-5 amino acids are removed from the C-terminus of the cytokine. Meprin A and meprin B cleaved IL-6 with micromolar affinities (Km of 4.7 and 12.0 uM, respectively) and with high efficiencies (kcat/Km of 0.2 and 2.5 (M-1 s-1) x 106 , respectively). These efficiency constants are among the highest for known meprin substrates. Madin-Darby Canine Kidney Cells transiently transfected with meprin α or meprin β constructs also cleave exogenous IL-6. Both human and murine IL-6 cleaved by meprin A or B are inactivated, as demonstrated by their decreased capability to stimulate proliferation of B9 cells. These results are consistent with the proposition that one function of meprin metalloproteinases is to modulate inflammation by inactivating IL-6.