The Role of p38 MAPK in Rhinovirus-Induced Monocyte Chemoattractant Protein-1 Production by Monocytic-Lineage Cells

Abstract

Viral respiratory infections are a major cause of asthma exacerbations and can contribute to the pathogenesis of asthma. Major group human rhinovirus enters cells by binding to the cell surface molecule ICAM-1 that is present on epithelial and monocytic lineage cells. The focus of the resulting viral infection is in bronchial epithelia. However, previous studies of the cytokine dysregulation that follows rhinovirus infection have implicated monocytic lineage cells in establishing the inflammatory environment even though productive infection is not a result. We have determined that human alveolar macrophages and human peripheral blood monocytes release MCP-1 upon exposure to human rhinovirus 16 (HRV16). Indeed, we have found p38 MAPK activation in human alveolar macrophages within 15 min of exposure to HRV16, and this activation lasts up to 1 h. The targets of p38 MAPK activation include transcriptional activators of the MCP-1 promoter. The transcription factor ATF-2, a p38 MAPK substrate, is phosphorylated 45 min after HRV16 exposure. Furthermore, IκBα, the inhibitor of the transcription factor NF-κB, is degraded. Prevention of HRV16 binding was effective in blocking p38 MAPK activation, ATF-2 phosphorylation, and MCP-1 release. This is the first report of a relationship between HRV16 exposure, MCP-1 release and monocytic-lineage cells suggesting that MCP-1 plays a role in establishing the inflammatory microenvironment initiated in the human airway upon exposure to rhinovirus.

Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias

“…In the context of human rhinovirus infection, which is frequently associated with asthma exacerbations, both epithelial cells and monocytes were found to be important sources of CXCL10; however, monocytes appear to be the dominant cell type (25). Additionally, studies comparing CXCL10 production by monocytes versus alveolar macrophages have documented similar chemokine production by the 2 cell types, and peripheral blood monocytes are considered appropriate cells to study CXCL10 gene expression (24,44). Having observed increased expression of CXCL10 in the BAL cells of a subset of severe asthmatics correlating strongly with IFNG expression, and given the utility of monocytes to study mechanisms of CXCL10 gene expression, we used the human monocytic cell line THP-1 as well as peripheral blood monocytes to assess CXCL10 mRNA and protein expression in the context of IFN-γ and CS.…”

“…CXCL10 can be secreted by multiple cell types, including airway epithelial cells, smooth muscle cells, monocytes, and macrophages (11). However, several studies have implicated monocytes/macrophages as possible drivers of CXCL10 expression in asthma (24,25).…”

Induction of Viral, 7-Methyl-Guanosine Cap-Independent Translation and Oncolysis by Mitogen-Activated Protein Kinase-Interacting Kinase-Mediated Effects on the Serine/Arginine-Rich Protein Kinase

“…PVSRIPO, PV type 1 (Sabin), CBV3, and CHICO were propagated in HeLa cells as described previously (18) and concentrated by centrifugation through a 100-kDa-cutoff spin column (Millipore). HRV16 was obtained from Y. Bochkov, University of Wisconsin, and propagated as described previously (28). 12-O-Tetradecanoylphorbol-13-acetate (TPA) (Tocris) was dissolved in dimethyl sulfoxide (DMSO).…”

Rhinovirus-Induced Macrophage Cytokine Expression Does Not Require Endocytosis or Replication

“…In untreated BMMs, stimulation with RV or UV-RV significantly increased transcript levels of the M1 cytokines TNF-a, CXCL1, IL-6, and IL-12 ( Figures 1C-1F). Replicationdeficient, UV-irradiated RV has been previously shown to be sufficient for macrophage/monocyte and epithelial cell cytokine production, indicating that viral replication is not required for this process (5).…”

“…However, it is conceivable that RV directly infects airway inflammatory cells. Recent studies indicate that inoculation of monocytes with RV induces cytokine expression in vitro (3)(4)(5)(6)(7)(8), although the level of viral replication in these cells is small or negligible. Recently, we demonstrated that, in ovalbumin (OVA)-sensitized and -challenged mice, RV colocalizes with eotaxin-and IL-4-positive lung macrophages (9), suggesting that lung macrophages may play a role in the airway inflammatory response to RV in vivo.…”