Search

Airway epithelial cells represent the primary cell target of respiratory syncytial virus (RSV) infection. They actively participate in the lung immune/inflammatory response that follows RSV infection by expressing chemokines, small chemotactic cytokines that recruit and activate leukocytes. Regulated on activation, normal T cell expressed, and presumably secreted (RANTES) is a member of the CC chemokine subfamily and is strongly chemotactic for T lymphocytes, monocytes, basophils, and eosinophils, cell types that are present or activated in the inflammatory infiltrate that follows RSV infection of the lung. RSV infection of airway epithelial cells induces RANTES expression by increasing gene transcription and stabilizing RNA transcripts. The signaling pathway regulating RANTES gene expression after RSV infection has not been determined. In this study, we examined the role of extracellular signal-regulated kinase (ERK) and p38, members of the mitogen-activated protein (MAP) kinase (MAPK) family, in RSV-induced RANTES production. RSV infection of alveolar epithelial cells induced increased phosphorylation and catalytic activity of ERK and the upstream kinases Raf-1 and MAP ERK kinase. Induction of the MAP signaling cascade required a replication-competent virus. RSV infection of alveolar epithelial cells also induced activation of p38 MAPK. Inhibition of ERK and p38 activation significantly reduced RSV-induced RANTES mRNA and protein secretion without affecting RANTES gene transcription or transcription factor activation. These results indicate that the MAPK signaling cascade regulates RANTES production in alveolar epithelial cells through a posttranscriptional mechanism. respiratory syncytial virus; chemokine; signal transduction; gene regulation; mitogen-activated protein kinase; regulated on activation; normal T cell expressed, and presumably secreted

The transcription factor nuclear factor (NF)-κB controls the expression of numerous respiratory syncytial virus (RSV)-inducible inflammatory and immunomodulatory genes. Using a BALB/c mouse model, the present article shows that RSV potently and specifically activates NF-&kappaB in vivo, a process that involves nuclear translocation of the subunits RelA, p50, and c-Rel in the lung. By depletion of alveolar macrophages (AMs) in BALB/c mice and use of C3H/HeJ mice lacking a functional Toll-like receptor (TLR)-4 signaling pathway, we demonstrate the existence of distinct but sequentially integrated RSV-inducible early NF-κB responses in the lung. The first response occurs early after RSV inoculation, is AM and TLR4 dependent, and is viral replication independent, whereas the second response involves epithelial cells and/or inflammatory cells, is TLR4 independent, and requires viral replication. NF-κB may be considered a central activator of not only inflammatory but also innate immune responses to RSV. [ABSTRACT FROM AUTHOR]

Mast cells and basophils contribute to induction and/or maintenance of eosinophilic inflammation by a variety of mechanisms, including IgE-dependent and IgE-independent processes. The latter include a variety of stimuli that have only recently been elucidated, including mechanisms triggered by bacteria, virus, fungi, complement, or autoantibodies. MCs, and basophils contribute to inflammation both directly through the release of inflammatory mediators, cytokines and growth factors and indirectly through the activation of structural cells. Accumulating evidence places MCs (and most probably basophils) in a position of importance in the pathogenesis of CRS, particularly in the pathogenesis and progression of NP (Fig. 1). Mechanisms other than conventional IgE-dependent activation of MCs are intriguing as potential mechanisms of eosinophilic inflammation in non-allergic CRS/NP. Although it is not possible using current pharmacologic approaches to completely isolate the effects of MCs or basophils in CRS and NP pathogenesis, it seems most likely that such approaches will eventually be available. It might be expected that one or both of these cells will be shown to play important roles, particularly considering their potential for activation by IgE and non-IgE mechanisms, their production of a broad array of inflammatory mediators, cytokines and growth factors, and their unique assortment of proteases.

Allergic diseases like atopic rhinitis, bronchial asthma, and urticaria are prevalent and on the rise. Mast cells are known to play a central role in the immediate phase reaction of allergic diseases through the IgE-mediated release of a variety of chemical mediators like histamine, leukotrienes, and prostaglandins. On the other hand, T lymphocytes, basophils and eosinophils are thought to be responsible in inducing the late phase response. Yet, recent studies show that the mast cell cannot be simplistically assigned a role in the immediate phase allergic response, and that this cell plays a crucial role in ongoing allergic inflammation, including the development of hyper-responsiveness. In the present article, the author will try to discuss the integrated roles of mast cells in IgE-mediated allergic inflammation with specific emphasis on the roles of mast cell-IgE networking and mast cell-structural cell interactions in the late phase allergic response and chronic allergic inflammation.