The interaction of human plasma fibrinogen with leukocyte integrins ␣ M  2 (CD11b/ CD18, Mac-1) and ␣ X  2 (CD11c/CD18, p150,95) is an important component of the inflammatory response. Previously, it was demonstrated that binding of fibrinogen to these integrins is mediated by ␥C, the globular C-terminal domain of the ␥ chain. In this study, evidence was found of another fibrinogen domain that can serve as a ligand for the 2 leukocyte integrins: ␣ E C, a homologous domain that extends the ␣ chains in a recently discovered subclass of fibrinogen known as fibrinogen-420. Recombinant ␣ E C supported strong adhesion and migration of cells expressing ␣ M  2 and ␣ X  2 , including nonactivated and activated U937 and THP-1 monocytoid cells, and neutrophils. Cells transfected with complementary DNA for these integrins also bound ␣ E C. The specificity of interaction was substantiated by inhibition of cell adhesion with antibodies against ␣ M , ␣ X , and  2 subunits. Also, neutrophil inhibitory factor, a specific inhibitor of ␣ M  2 and ␣ X  2 function, efficiently blocked cell adhesion to ␣ E C. In ␣ M  2 and ␣ X  2 , the I domain is the binding site for ␣ E C, since ␣ E C bound to recombinant ␣ M I and ␣ X I domains in a dose-dependent and saturable manner. Synthetic peptides that duplicated sequences ␥190 to 202 and ␥377 to 395, previously considered putative binding sites in ␥C, effectively inhibited ␣ M  2 -and ␣ X  2 -mediated adhesion to ␣ E C, suggesting that recognition of ␣ E C by the I domain involves structural features in common with those of ␥C. These findings identify ␣ E C as a second domain in fibrino
IntroductionIn addition to its function in the coagulation and hemostatic systems, plasma protein fibrinogen (Fg) also participates in inflammatory responses. This function of Fg depends on its ability to interact with leukocyte receptors. On inflammatory challenge, Fg mediates adhesive and migratory reactions of leukocytes, such as leukocyte attachment to the vessel wall and subsequent transmigration through the endothelium into a subendothelial matrix. [1][2][3] In addition, fibrinogen and fibrin deposited at sites of vascular injury and within tissues 4,5 promote accumulation of inflammatory cells. 6,7 The accessory role of Fg in inflammation was documented by in vivo studies in which congenital afibrinogenemia in patients or experimental depletion of Fg from the circulation in animals altered the manifestation of inflammatory responses. [8][9][10][11][12] The interaction of leukocytes with Fg is mediated by 2 transmembrane receptors that belong to the integrin gene superfamily: ␣ M  2 (CD11b/CD18, Mac-1) and ␣ X  2 (CD11c/CD18, p150,95). Abundantly expressed on monocytes and neutrophils and induced on lymphocytes during their activation, integrin ␣ M  2 is primarily responsible for leukocyte adhesion to Fg. 13 Studies in mice deficient in ␣ M  2 demonstrated that fibrinogen-dependent inflammatory reactions were significantly curtailed in these animals. 14 Specifically, the mice failed to...
