Upregulation of tissue factor in monocytes by cleaved high molecular weight kininogen is dependent on TNF- and IL-1

Khan MM, Liu Y, Khan ME, Gilman ML, Khan ST, Bromberg M, Colman RW. Upregulation of tissue factor in monocytes by cleaved high molecular weight kininogen is dependent on TNFand IL-1 . Am J Physiol Heart Circ Physiol 298: H652–H658, 2010. First published December 4, 2009; doi:10.1152/ajpheart.00825.2009.—Inflammatory bowel disease and arthritis are associated with contact activation that results in cleavage of kininogen to form high molecular weight kininogen (HKa) and bradykinin. We have previously demonstrated that HKa can stimulate inflammatory cytokine and chemokine secretion from human monocytes. We now show that HKa can upregulate tissue factor antigen and procoagulant activity on human monocytes as a function of time (1–4 h) and HKa concentration (75–900 nM). The amino acid sequence responsible to block HKa effects is G440–H455. The HKa receptor macrophage-1 (Mac-1; CD11b18) is the binding site as shown by inhibition by a monoclonal antibody to CD11b/18. Chemical inhibitors of JNK, ERK, and p38 signaling pathways block cell signaling, as does an inhibitor to the transcription factor NFB. A combination of monoclonal antibodies to TNFand IL-1 but neither alone inhibited the HKa induction of tissue factor. These results suggest that HKa mimics LPS by triggering a paracrine pathway in monocytes that depends on TNFand IL-1 . Antibodies to kininogen or peptidomimetics might be a useful and safe therapy in inflammatory diseases or sepsis involving cytokines.