Upregulation of tissue factor in monocytes by cleaved high molecular weight kininogen is dependent on TNF-alpha and IL-1beta.
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 NF-kappaB. A combination of monoclonal antibodies to TNF-alpha and IL-1beta 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 TNF-alpha and IL-1beta. Antibodies to kininogen or peptidomimetics might be a useful and safe therapy in inflammatory diseases or sepsis involving cytokines.
Khan
Mohammad M
MM
The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
Liu
Yuchuan
Y
Khan
Munir E
ME
Gilman
Megan L
ML
Khan
Sabina T
ST
Bromberg
Michael
M
Colman
Robert W
RW
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D000911:Antibodies, Monoclonal; D053583:Interleukin-1beta; D019679:Kininogen, High-Molecular-Weight; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013925:Thromboplastin; D020929:Mitogen-Activated Protein Kinase Kinases