Lipopolysaccharide-induced activation of beta 2-integrin function in macrophages requires Irak kinase activity, p38 mitogen-activated protein kinase,and the Rap1 GTPase

Lipopolysaccharide (LPS), a component of the outer membrane of gram-negativ e bacteria, is a potent activator of macrophages. Besides inducing many tra nscriptional pathways, LPS also elicits rapid morphological changes such as cell spreading. Here we have investigated the signaling pathway that contr ols macrophage beta2-integrin-dependent spreading in response to LPS. We sh ow that inhibition of the adapter protein MyD88, the interleukin-1 receptor -associated kinase Irak, the p38 mitogen-activated protein kinase, or the R as-like GTPase Rap1 blocks LPS-induced spreading. In addition, Irak activat es p38 and stimulates p38-dependent spreading. The activation of p38 by Ira k requires Irak's kinase activity. We find that p38 controls spreading inde pendently of its role in transcription but rather through activation of Rap 1. Together, our results suggest that beta2-integrin-dependent spreading of macrophages in response to LPS is controlled by a linear signaling pathway via MyD88, Irak, p38, and Rap1.