Rhinovirus-induced Activation of Intracellular Signaling Events in Human Monocytes and Alveolar Macrophages*1

RATIONALE: Respiratory infections with rhinovirus (RV) are a major cause of asthma exacerbations and may contribute to the overall pathogenesis of asthma.Alveolar macrophages, the predominant immune cell in the airway lumen, have been implicated in promoting cytokine dysregulation within the inflammatory microenvironment in response to RV respiratory infections.Given the importance of RV in the pathobiology of asthma and the paucity of information on the intracellular mechanisms by which RV activates macrophages, this study evaluated the activity of MAP Kinases and CREB, a transcription factor critical for the induction of several proinflammatory cytokines, following monocyte or macrophage exposure to RV. METHODS: Primary human monocytes or alveolar macrophages were incubated with purified human RV-16 (MOI=0.01-100)for 5-120min.Cell lysates were immunoblotted with antibodies for activated (phosphorylated) MAP Kinases or CREB.RESULTS: Exposure of human monocytic cells to RV results in the activation of both JNK and p38 MAP Kinases in a time-and dose-dependent manner (N=3).However ERK1 and ERK2 activation following RV stimulation is not discernable.Furthermore, RV-induces phosphorylation of the CREB transcription factor.Lastly, pretreatment of human monocytic cells with SB202190, a selective inhibitor of p38 MAP Kinase, diminishes RV-induced CREB activation (N=3).CONCLUSIONS: These studies demonstrate that RV interaction with monocytic cells stimulates the phosphorylation and activation of MAP Kinase pathways, and CREB and suggest that this is an important mechanism regulating macrophage cytokine elaboration during virus-induced exacerbations of asthma.