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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2260.)
© 2006 American Heart Association, Inc.

Vascular Biology

High-Molecular-Weight Kininogen Fragments Stimulate the Secretion of Cytokines and Chemokines Through uPAR, Mac-1, and gC1qR in Monocytes

Mohammad M. Khan; Harlan N. Bradford; Irma Isordia-Salas; Yuchuan Liu; Yi Wu; Ricardo G. Espinola; Berhane Ghebrehiwet; Robert W. Colman

From The Sol Sherry Thrombosis Research Center (M.M.K., H.N.B., I.I.-S., Y.L., Y.W., R.G.E., R.W.C.), Temple University School of Medicine, Philadelphia, Pa; Department of Medicine (B.G.), State University of New York, Stony Brook, NY.

Correspondence to Robert W. Colman, MD, The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3400 N. Broad St, OMS 418, Philadelphia, PA 19140. E-mail colmanr{at}temple.edu

Objective— Plasma high-molecular-weight kininogen (HK) is cleaved in inflammatory diseases by kallikrein to HKa with release of bradykinin (BK). We postulated a direct link between HKa and cytokine/chemokine release.

Methods and Results— HKa, but not BK, releases cytokines tumor necrosis factor (TNF)-, interleukin (IL)-1ß, IL-6, and chemokines IL-8 and MCP-1 from isolated human mononuclear cells. At a concentration of 600 nM, glutathione-S-transferase (GST) fusion proteins of kininogen domain 3 (D3), a fragment of domain 3, E7P (aaG255-Q292), HK domain 5 (D5), the D5 recombinant peptides HG (aa K420-D474) and HGK (aa H475-S626) stimulated secretion of IL-1ß from mononuclear cells. Monoclonal antibodies (MAbs) specific for D5 or specific for D3 blocked release of IL-1ß by HKa, supporting the importance of both domains. Antibodies to HK receptors on leukocytes including Mac-1, LFA-1, uPAR, and C1qR inhibited IL-1ß secretion induced by tKa 98%, 89%, 85%, and 62%, respectively. Fractionation of mononuclear cells identified the responsible cell, a blood monocyte. Inhibitors of signaling pathways NFkB, JNK, and p38 but not extracellular signal-regulated kinase (ERK) decreased cytokine release from mononuclear cells. HKa increased the synthesis of IL-1ß as deduced by an increase of IL-1ß mRNA at 1 to 2 hours.

Conclusions— HKa domains 3 and 5 may contribute to the pathogenesis of inflammatory diseases by releasing IL-1ß from human monocytes using intracellular signaling pathways initiated by uPAR, ß2 integrins and gC1qR.

Cleavage of kininogen occurs in inflammation but its pathogenic mechanism is not clear. HKa releases inflammatory cytokines and chemokines from human monocytes. Receptors involved include uPAR, Mac-1, LFA-1, and gC1qR. Signaling pathways used are NFkB, p38, and JNK kinases. HKa is a target for therapy of inflammation.

Key Words: chemokines • cytokines • kininogen • monocytes • uPAR

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