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Molecular and Cellular Biology, July 2007, p. 4603-4616, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.00223-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

ABIN-3: a Molecular Basis for Species Divergence in Interleukin-10-Induced Anti-Inflammatory Actions{triangledown}

Brian K. Weaver, Erwin Bohn, Barbi A. Judd, M. Pilar Gil, and Robert D. Schreiber*

Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110

Received 6 February 2007/ Returned for modification 12 April 2007/ Accepted 25 April 2007

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-{kappa}B 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-{kappa}B. Conversely, human ABIN-3 was capable of inhibiting NF-{kappa}B 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 I{kappa}B{alpha}, the activation of NF-{kappa}B, 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-{kappa}B in human macrophages yet is inoperative in mice and represents a basis for species-specific differences in IL-10 actions.

* Corresponding author. Mailing address: Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: (314) 362-8747. Fax: (314) 362-8888. E-mail: schreiber{at}pathology.wustl.edu

{triangledown} Published ahead of print on 7 May 2007.

Molecular and Cellular Biology, July 2007, p. 4603-4616, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.00223-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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