ABIN-3: a molecular basis for species divergence in interleukin-10-induced anti-inflammatory actions.
Whereas interleukin-10 (IL-10) is an anti-inflammatory cytokine known to regulate macrophage activation, its full mechanism of action remains incompletely defined. In a screen to identify novel IL-10-induced genes, we cloned the mouse ortholog of human ABIN-3 (also termed LIND). ABIN-3 expression was induced selectively by IL-10 in both mouse and human mononuclear phagocytes coordinately undergoing proinflammatory responses. In contrast to the previously characterized ABINs, mouse ABIN-3 was incapable of inhibiting NF-kappaB activation by proinflammatory stimuli. Generation and analysis of ABIN-3-null mice demonstrated that ABIN-3 is unnecessary for the anti-inflammatory effects of IL-10 as well as for proper negative regulation of NF-kappaB. Conversely, human ABIN-3 was capable of inhibiting NF-kappaB activation in response to signaling from Toll-like receptor, IL-1, and tumor necrosis factor. Enforced expression of human ABIN-3 in human monocytic cells suppressed the cytoplasmic degradation of IkappaBalpha, the activation of NF-kappaB, and the induction of proinflammatory genes. Comparative sequence analyses revealed that mouse ABIN-3 lacks a complete ABIN homology domain, which was required for the functional activity of human ABIN-3. ABIN-3 is, thus, an IL-10-induced gene product capable of attenuating NF-kappaB in human macrophages yet is inoperative in mice and represents a basis for species-specific differences in IL-10 actions.
Weaver
Brian K
BK
Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Bohn
Erwin
E
Judd
Barbi A
BA
Gil
M Pilar
MP
Schreiber
Robert D
RD
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D014644:Genetic Variation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D020298:U937 Cells
D048868:Adaptor Proteins, Signal Transducing; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011506:Proteins; C426747:TNIP3 protein, human; C503281:Tnip2 protein, mouse; D016753:Interleukin-10; D051550:I-kappa B Kinase