Ligand binding to monocyte alpha 5 beta 1 integrin activates the alpha 2 beta 1 receptor via the alpha 5 subunit cytoplasmic domain and protein kinase C.
Regulation of the functional status of integrin receptors plays a critical role in inflammation and tissue remodeling, as it affects cell adherence and cytokine secretion. We have previously shown that in monocytes the binding of collagen to the alpha 2 beta 1 integrin induces the release of IL-1, an event that is potentiated by binding of fibronectin (Fn) to the alpha 5 beta 1 integrin. In this study, we have investigated the mechanisms leading to this phenomenon. Fn binding to alpha 5 beta 1 induced intracellular signals which increased the alpha 2 beta 1-dependent adhesiveness of monocytes to collagen without modifications of alpha 2 beta 1 expression. By using Abs against the intracellular region of the alpha 5 subunit of the alpha 5 beta 1 receptor, and specific inhibitors of protein kinase C (PKC), we found that the potentiation effect of Fn on monocyte IL-1 production and their adherence to collagen was dependent on an intact alpha 5 subunit cytoplasmic domain, and required PKC activation. Although the alpha 2 beta 1 could be activated by several intracellular second messengers, including protein kinase A and intracellular calcium, the potentiating effect of Fn was mediated only by PKC. These data provide an example of a novel regulatory mechanism: potentiation of beta 1 integrin-mediated events as a result of ligand binding to another integrin of the same class. They also show that the intracellular region of alpha 5 beta 1 plays a critical role in transducing signals generated by ligand binding to alpha 5 beta 1.
Pacifici
R
R
Division of Endocrinology and Bone Diseases, Washington University School of Medicine, St. Louis, MO 63110.
Roman
J
J
Kimble
R
R
Civitelli
R
R
Brownfield
C M
CM
Bizzarri
C
C
D002118:Calcium / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D003593:Cytoplasm / Q000502:physiology; D004357:Drug Synergism; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D016023:Integrins / Q000378:metabolism* / Q000502:physiology*; D007375:Interleukin-1 / Q000378:metabolism; D008024:Ligands; D009000:Monocytes / Q000378:metabolism*; D010446:Peptide Fragments / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology*; D038981:Receptors, Collagen; D017469:Receptors, Fibronectin / Q000378:metabolism*; D015398:Signal Transduction
D005353:Fibronectins; D016023:Integrins; D007375:Interleukin-1; D008024:Ligands; D010446:Peptide Fragments; D038981:Receptors, Collagen; D017469:Receptors, Fibronectin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium