EC3, a heterodimeric disintegrin from Echis carinatus, inhibits human and murine alpha4 integrin and attenuates lymphocyte infiltration of Langerhans islets in pancreas and salivary glands in nonobese diabetic mice.
The venom of Echis carinatus suchoreki contains a monomeric disintegrin echistatin (Mr 5,500 Da) that strongly inhibits alphaIIbbeta3, alphavbeta3, and alpha5beta1 integrins and a heterodimeric disintegrin called EC3 (M(r) 14,762 Da). At nanomolar concentration, EC3 inhibits adhesion of human cell lines expressing alpha4beta1 and alpha4beta7 to immobilized VCAM-1; it has a lower inhibitory effect on alpha5beta1-mediated cell adhesion. In this study, we demonstrated that EC3, in contrast to echistatin, inhibited binding of monoclonal anti-alpha4 and anti-alpha5 antibodies to cells expressing alpha4beta7. In a dose-dependent manner and to the same extent, EC3 inhibited adhesion of Jurkat cells and murine splenic lymphocytes to immobilized VCAM-1, whereas echistatin was not active. EC3 injected intraperitoneally into nonobese diabetic (NOD mice) suppressed development of insulitis and sialoadenitis, whereas echistatin had no significant effect. We propose that the effect of EC3 is mediated, at least, in part, by blocking alpha4beta1 and alpha4beta7 on murine lymphocytes.
Brando
C
C
Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania, 19140, USA.
Marcinkiewicz
C
C
Goldman
B
B
McLane
M A
MA
Niewiarowski
S
S
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D019483:Disintegrins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D039441:Integrin alpha4; D036341:Intercellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D019169:Jurkat Cells; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D012469:Salivary Glands / Q000276:immunology* / Q000473:pathology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000276:immunology; D014407:Tumor Cells, Cultured; D014757:Viper Venoms / Q000737:chemistry / Q000494:pharmacology
D015703:Antigens, CD; D019483:Disintegrins; C119089:EC3 protein, Echis carinatus; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D014757:Viper Venoms; C057986:echistatin; D039441:Integrin alpha4