αVβ3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-κB activation

Alexander S. Antonov, Galina N. Antonova, David H Munn, Nahid F Mivechi, Rudolf Lucas, John D. Catravas, Alexander Dmitriyevich Verin

Research output: Contribution to journalArticle

53 Citations (Scopus)

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 αVβ3 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 αVβ3 ligation results in sustained increases of the transcription factor NF-κB DNA-binding activity, as compared with control isotype-matched IgG1. Activation of NF-κB parallels the increase of NF-κB-dependent pro-inflammatory cytokine mRNA expression in MDMs isolated from individual donors, for example, TNF-α (8- to 28-fold), IL-1β (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 αVβ3 receptor, treatment with TNF-α (10 ng/ml) or LPS (200 ng/ml, 1,000 EU) results in the enhanced and synergistic activation of NF-κB and LPS-induced TNF-α secretion. As additional controls, an inhibitor of αVβ3 integrin, cyclic RGD (10 μg/ml; IC50 = 7.6 μM), attenuates the effects of αVβ3 ligation, and the natural ligand of αVβ3 integrin, vitronectin, reproduces the effects of αVβ3 activation by an immobilizing anti-αVβ3 integrin mAb. We hypothesize that αVβ3 activation can maintain chronic inflammatory processes in pathological conditions and that the loss of αVβ3 ligation will allow macrophages to escape from the inflammatory state.

Original languageEnglish (US)
Pages (from-to)469-476
Number of pages8
JournalJournal of Cellular Physiology
Volume226
Issue number2
DOIs
StatePublished - Feb 1 2011

Fingerprint

Macrophages
Phosphatidylinositol 3-Kinases
Integrins
Chemical activation
Ligation
Vitronectin
Interleukin-15
Messenger RNA
Interleukin-5
Pathologic Processes
Interleukin-8
Interleukin-1
Interleukin-10
Inhibitory Concentration 50
Interleukin-2
Monocytes
Interleukin-6
Blood
Transcription Factors
Immunoglobulin G

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

αVβ3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-κB activation. / Antonov, Alexander S.; Antonova, Galina N.; Munn, David H; Mivechi, Nahid F; Lucas, Rudolf; Catravas, John D.; Verin, Alexander Dmitriyevich.

In: Journal of Cellular Physiology, Vol. 226, No. 2, 01.02.2011, p. 469-476.

Research output: Contribution to journalArticle

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