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-κB 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-κB. Conversely, human ABIN-3 was capable of inhibiting NF-κB 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 IκBα, the activation of NF-κB, 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-κB in human macrophages yet is inoperative in mice and represents a basis for species-specific differences in IL-10 actions.
The proinflammatory functions of monocytes and macrophages represent an important component of host responses to infection. These responses occur, in part, as a consequence of the interaction between pathogen-associated molecular patterns (PAMPs) expressed by infectious agents and cellular pathogen recognition receptors (PRRs) expressed by the host. PRRs are a large and diverse group of microbial sensors that include the membrane-associated Toll-like receptors (TLRs) and the cytoplasmic NOD-like receptors and RIG-like helicases (1, 38, 46). In macrophages, engagement of a PRR by its PAMP ligand, e.g., bacterial lipopolysaccharide (LPS), peptidoglycan (PGN), or viral double-stranded RNA, leads to triggering of mitogen-activated protein kinase (MAPK) signaling cascades and activation of transcription factors belonging to the NF-κB, the AP-1, and the IRF families (1, 40, 58). These signaling processes effect the induction of genes that promote the inflammatory response including cytokines, chemokines, and enzymes responsible for producing reactive oxygen and nitrogen species.
See article for completed abstract
Weaver, Brian K., Erwin Bohn, Barbi A. Judd, M. Pilar Gil, and Robert D. Schreiber. "ABIN-3: a molecular basis for species divergence in interleukin-10-induced anti-inflammatory actions." Molecular and cellular biology 27, no. 13 (2007): 4603-4616.
Molecular and cellular biology