Relationships between Cytokine Profiles and Signaling Pathways (IκB Kinase and p38 MAPK) in Parainfluenza Virus-Infected Lung Fibroblasts.

Respiratory viruses such as parainfluenza virus (PIV) in individuals with certain genetic predispositions in early life are associated with the induction of wheezing, which can progress to the development of asthma. It has been suggested that aberrant production of various cytokines due to viral infection are associated with virus-induced asthma. However, the mechanisms of how respiratory viruses induce and exacerbate asthma have yet to be clarified. To examine cytokine responses to PIV infection, we assessed 27 cytokine levels released from PIV-infected human fetal lung fibroblasts. In addition, we examined relationships between these cytokine responses and signaling pathways (IκB kinase and p38 MAPK) in PIV-infected cells. At 24 h after infection, PIV-infected cells significantly released a number of cytokines, namely, proinflammatory cytokines [interleukins (IL)-1β, IL-6, and tumor necrosis factor-α], anti-inflammatory cytokine (IL-1ra), Th1 cytokines (interferon-γ, and IL-2), Th2 cytokines (IL-4, IL-5, and IL-10), granulopoiesis-inducing cytokines (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor), neutrophil recruitment-inducing cytokines (IL-8 and interferon-inducible protein-10), and eosinophil recruitment-inducing cytokines (eotaxin and regulated on activation normal T-cell expressed and secreted). PIV infection enhanced phosphorylation of both IκB and p38 MAPK, but not Akt, in the cells. Signaling pathway inhibitors, BMS-345541 (a specific IκB kinase inhibitor) and SB203580 (a specific p38 MAPK inhibitor), significantly suppressed release of these cytokines from PIV-infected cells. The results indicate that PIV infection induces aberrant production and release of various cytokines through IκB kinase and p38 MAPK pathways in human lung fibroblasts. Overproduction and imbalance of these cytokines may be partially associated with the pathophysiology of virus-induced asthma.