INTERLEUKIN-6 DOWN-REGULATES FACTOR-XII PRODUCTION BY HUMAN HEPATOMA-CELL LINE (HEPG2)

Involvement of the contact system of coagulation in the pathogenesis o f various inflammatory diseases is suggested by reduced plasma levels of factor XII (Hageman factor) and prekallikrein generally considered to result from activation of the contact system. However, in many of t hese diseases patients develop an acute-phase response and, therefore, an alternative explanation for the decreased levels of factor XII cou ld be the downregulation of factor XII gene expression in the liver as described for negative acute-phase proteins. We report here that inte rleukin-6 (IL-6), the principal cytokine mediating the synthesis of mo st acute-phase proteins in the liver, downregulates the production of factor XII by the human hepatoma cell line HepG2 by up to 75%. The dec rease in protein secretion correlated with an equivalent decrease of f actor XII mRNA likely indicating a pretranslational control of factor XII gene expression by IL-6. Downregulation of factor XII production b y IL-6 in vitro parallelled that of transthyretin, a known negative ac ute-phase protein. Moreover, we show that, in patients developing an a cute-phase response after immunotherapy with IL-2, plasma levels of fa ctor XII correlate (r = .76, P < .0001) with those of transthyretin. T aken together, these results suggest that factor XII behaves as a nega tive acute-phase protein. (C) 1997 by The American Society of Hematolo gy.