CD11b/CD18 mediates the neutrophil chemotactic activity of fibrin degradation product D domain.
Coagulation and fibrinolysis universally accompany tissue injury and repair. The accumulation of regionally generated fibrin degradation products (FDP) may modify the local inflammatory response. We have found FDP to be potent neutrophil chemotaxins. We separated plasmin FDP by chromatofocusing and found chemotactic activity limited to fractions containing the fibrinogen D domain (D-D dimer and D monomer). The bioactivity of the D-D dimer did not require an intact cross link site as removal of this sequence with puff adder venom or hypocalcemic plasmic digestion did not decrease chemotaxis. Peptide inhibition studies confirmed that the chemotactic region did not involve terminal gamma chain sequences or alpha chain RGD motifs. The internal gamma chain peptide KYGWTVFQKRLDGSV (P1), known to bind CD11b/CD18, exhibited concentration dependent chemotactic activity. Similarly, monoclonal antibodies directed against CD11b/CD18 blocked PMN migration to FDP without similar inhibition of chemotaxis to IL-8 or LTB4. Thus, neutrophil chemotaxis to FDP is mediated by interactions between the fibrinogen D domain and CD11b/CD18.
Gross
T J
TJ
Department of Internal Medicine, University of Iowa College of Medicine Iowa City, USA.
Leavell
K J
KJ
Peterson
M W
MW
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D019281:Dimerization; D005338:Fibrin Fibrinogen Degradation Products / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D000933:Antifibrinolytic Agents; D015703:Antigens, CD; D018821:CD18 Antigens; D005338:Fibrin Fibrinogen Degradation Products; D016209:Interleukin-8; D016177:Macrophage-1 Antigen; D009842:Oligopeptides; D010446:Peptide Fragments; C036309:fibrin fragment D; D009240:N-Formylmethionine Leucyl-Phenylalanine; C047981:arginyl-glycyl-aspartic acid