p38 Mitogen-Activated Protein Kinase and c-Jun-NH2-Terminal Kinase Regulate RANTES Production by Influenza Virus-Infected Human Bronchial Epithelial Cells

Abstract

Airway epithelial cells which are the initial site of influenza virus (IV) infection are suggested to participate in airway inflammatory response by expressing various cytokines including RANTES; however, the intracellular signal that regulates RANTES expression has not been determined. In the present study, we examined the role of p38 mitogen-activated protein (MAP) kinase, extracellular signal-regulated kinase (Erk), and c-Jun-NH2-terminal kinase (JNK) in RANTES production by IV-infected human bronchial epithelial cells. The results showed that IV infection induced increases in p38 MAP kinase, and Erk and JNK phosphorylation and activity. SB 203580, PD 98059, and CEP-1347 attenuated IV-infection induced p38 MAP kinase activity, Erk activity, and JNK activity, respectively. SB 203580 and CEP-1347 attenuated RANTES production by 45.3% and 45.2%, respectively, but a combination of these inhibitors additively attenuated by 69.1%. In contrast, PD 98059 did not attenuate. Anti-IL-1α mAb, anti-IL-1β mAb, anti-TNF-α mAb, anti-IL-8 mAb, anti-IFN-β mAb, anti-RANTES mAb, and a combination of these mAbs did not affect IV infection-induced increases in p38 MAP kinase, Erk, and JNK phosphorylation, indicating that each cytokine neutralized by corresponding Ab was not involved in IV infection-induced phosphorylation of MAP kinases. N-acetylcysteine (NAC) did not affect IV infection-induced increases in MAP kinase phosphorylation, whereas NAC attenuated RANTES production by 18.2%, indicating that reactive oxygen species may act as a second messenger leading to RANTES production via p38 MAP kinase- and JNK-independent pathway. These results indicate that p38 MAP kinase and JNK, at least in part, regulate RANTES production by bronchial epithelial cells.

Induction of Proinflammatory Cytokines in Primary Human Macrophages by Influenza A Virus (H5N1) Is Selectively Regulated by IFN Regulatory Factor 3 and p38 MAPK

“…Previous reports have shown that p38 kinase regulates influenza virus-induced RANTES expression in bronchial epithelial cells (39) and is involved in TNF-␣ production during H5N1 infection (18). Therefore, we explored the effect of IRF3 knockdown and p38 kinase inhibitor treatment both singly and in combination on H5N1-induced cytokine and chemokine expression.…”

Differential proteomic analysis of respiratory samples from patients suffering from influenza

“…It has been shown that p38 MAPK and JNK, but not ERK1/2, regulate RANTES expression in influenza virus-infected bronchial epithelial cells. Moreover, MAPK/ERK kinase-specific inhibitors have been reported to inhibit the nuclear export of viral ribonucleoprotein complexes and impair the activity of nuclear-export protein, NEP/NS2, in the virus replication cycle [20]. The zinc finger is a novel motif found in Zinc finger proteins which bind to DNA.…”

“…These results are consistent with Andrea L. Kroeker's study [19] who reported that the down regulated proteins generally belong to cell adhesion and lipid metabolism. The proteins from pandemic influenza A/H1N1/2009 are MAPK7, Zinc finger proteins, Pyruvate dehydrogenase kinases and Beta-defensin 108B are mostly involved in anti-viral mechanism [10,20,28] and also help in host defense system. The proteins from influenza type B majorly IFIT2 along with Interleukin-1 receptor-associated kinase (IRAK) plays a central role in cell signaling processes as cited earlier [9,18].…”

Signaling Pathways Involved In Dengue-2 Virus Infection Induced RANTES Overexpression

“…RANTES representing by its chemotactic activity for eosinophils plays a pivotal role in the induction of airway inflammation of asthmatics through the recruitment of eosinophils to the inflammation site of airway after influenza virus infection [38] . Whether RANTES secretion induced by dengue virus infection of liver cells can recruit immune cells deserves further clarification.…”

“…In a previous study, HIV infection can activate RANTES through phosphorylation of Erk [37] . And Influenza virus infection can up-regulate RANTES expression through p38 and JNK [38] . Dengue virus can induce DNA binding activity of NF-IL-6 and up-regulates RANTES expression [9] .…”