?V?3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-?B activation.

ABSTRACT: 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 ?V?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 ?V?3 ligation results in sustained increases of the transcription factor NF-?B DNA-binding activity, as compared with control isotype-matched IgG(1). Activation of NF-?B parallels the increase of NF-?B-dependent pro-inflammatory cytokine mRNA expression in MDMs isolated from individual donors, for example, TNF-? (8- to 28-fold), IL-1? (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 ?V?3 receptor, treatment with TNF-? (10?ng/ml) or LPS (200?ng/ml, 1,000?EU) results in the enhanced and synergistic activation of NF-?B and LPS-induced TNF-? secretion. As additional controls, an inhibitor of ?V?3 integrin, cyclic RGD (10?µg/ml; IC(50)?=?7.6?µM), attenuates the effects of ?V?3 ligation, and the natural ligand of ?V?3 integrin, vitronectin, reproduces the effects of ?V?3 activation by an immobilizing anti-?V?3 integrin mAb. We hypothesize that ?V?3 activation can maintain chronic inflammatory processes in pathological conditions and that the loss of ?V?3 ligation will allow macrophages to escape from the inflammatory state.

SUBMITTER: Antonov AS 

PROVIDER: S-EPMC3235728 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature