Viral Induction of Inflammatory Cytokines in Human Epithelial Cells Follows a p38 Mitogen-Activated Protein Kinase-Dependent but NF-κB-Independent Pathway

Abstract

The initial step in an immune response toward a viral infection is the induction of inflammatory cytokines. This innate immune response is mediated by expression of a variety of cytokines exemplified by TNF-α and IL-1β. A key signal for the recognition of intracellular viral infections is the presence of dsRNA. Viral infections and dsRNA treatment can activate several signaling pathways including the protein kinase R pathway, mitogen-activated protein kinase (MAPK) pathways, and NF-κB, which are important in the expression of inflammatory cytokines. We previously reported that activation of protein kinase R was required for dsRNA induction of TNF-α, but not for IL-1β. In this study, we report that activation of the p38 MAPK pathway by respiratory viral infections is necessary for induction of inflammatory cytokines in human bronchial epithelial cells. Inhibition of p38 MAPK by two different pharmacological inhibitors showed that expression of both TNF-α and IL-1β required activation of this signaling pathway. Interestingly, inhibition of NF-κB did not significantly reduce viral induction of either cytokine. Our data show that, during the initial infections of epithelial cells with respiratory viruses, activation of the p38 MAPK pathway is associated with induction of inflammation, and NF-κB activation may be less important than previously suggested.

Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells

“…dsRNA is produced by most viruses during replication which recognizes the TLR3 on the cell membrane, upon binding and activation of the TLR3, dsRNA activates the NFκB pathway [47]. It is also known that dsRNA is closely associated with the interferon (IFN) system in host defense [48] and innate cytokine induction in lung epithelial cells [22,27]. It is interesting to find that after initial recognition of the pathogen by the receptors on the cells membrane, the signaling pathways activated by the virus and bacteria merges and cross-talk between the pathways occurred [49,50].…”

“…LPS, a major component of the outer membrane of gram-negative bacteria, and dsRNA, a viral mimetic, induce a potent inflammatory reaction by activation of several intracellular signaling transduction pathways and leads to the expression of proinflammatory cytokines and chemokines [20][21][22][23]. Addition of LPS or dsRNA to the cells rapidly induces phosphorylation of mitogen-activated protein kinase (MAPK) pathways, p38 and c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinases (ERK).…”

Respiratory Syncytial Virus Infection of Human Lung Endothelial Cells Enhances Selectively Intercellular Adhesion Molecule-1 Expression

“…The activity of the MEK, ERK and p38 kinase in RSV-infected epithelial cells has been linked to RSV replication, IL-8 release, and posttranscriptional RANTES gene expression, respectively (35,46,47). Moreover, it was reported that expression of TNF-␣ and IL-1␤ in RSV-infected epithelial cells required the activation of the p38 MAPK pathway (48). Our data supply evidence that only the p38 MAPK pathway must be in an active state to allow for RSV-dependent ICAM-1 up-regulation.…”

B‐cell‐activating factor expressions in salivary epithelial cells after dsRNA virus infection depends on RNA‐activated protein kinase activation

“…Interestingly, activation of a human T-cell line with 12-O-tetradecanoylphorbol-13-acetate and ionomycin induces BAFF expression through a signal transduction pathway involving p38 MAPK [23]. Some reports have previously shown that the activation of p38 MAPK depends on the serotype of reovirus and the type of cell infected [24][25][26]. Indeed, the serotype used in this study was the T1 serotype 1 prototype strain Lang, which is known not to activate p38 MAPK [24].…”