αVβ3 Integrin Regulates Macrophage Inflammatory Responses via PI3 Kinase/Akt-Dependent NF-κB Activation

Controlling macrophage responses to pathogenic stimuli is critical for prevention of and recovery from the inflammatory state associated with the pathogenesis of many diseases. The adhesion receptor alpha V beta 3 integrin is thought to be an important receptor that regulates macrophage differentiation and macrophage responses to external signaling, but it has not been previously identified as a contributor to macrophage-related inflammation. Using an in vitro model of human blood monocytes (Mo) and monocyte-derived macrophages (MDMs) we demonstrate that alpha V beta 3 ligation results in sustained increases of the transcription factor NF-kappa B DNA-binding activity, as compared with control isotype-matched IgG(1). Activation of NF-kappa B parallels the increase of NF-kappa B-dependent pro-inflammatory cytokine mRNA expression in MDMs isolated from individual donors, for example, TNF-alpha. (8- to 28-fold), IL-1 beta (15- to 30-fold), IL-6 (2- to 4-fold), and IL-8 (5- to 15-fold) whereas there is more than a 10-fold decrease in IL-10 mRNA level occurs. Upon ligation of the alpha V beta 3 receptor, treatment with TNF-alpha (10 ng/ml) or LPS (200 ng/ml, 1,000 EU) results in the enhanced and synergistic activation of NF-kappa B and LPS-induced TNF-alpha secretion. As additional controls, an inhibitor of alpha V beta 3 integrin, cyclic RGD (1 0 mu g/ml; IC50 = 7.6 mu M), attenuates the effects of alpha V beta 3 ligation, and the natural ligand of alpha V beta 3 integrin, vitronectin, reproduces the effects of alpha V beta 3 activation by an immobilizing anti-alpha V beta 3 integrin mAb. We hypothesize that alpha V beta 3 activation can maintain chronic inflammatory processes in pathological conditions and that the loss of alpha V beta 3 ligation will allow macrophages to escape from the inflammatory state. J. Cell. Physiol. 226: 469-476, 2011. (C) 2010 Wiley-Liss, Inc.