Mitogen-activated protein kinases (MAPKs) regulate IL-6 over-production during concomitant influenza virus and Staphylococcus aureus infection

Abstract

Bacterial super-infections are a major complication of influenza virus (IV) infections and often lead to severe pneumonia. One hallmark of IV-associated Staphylococcus aureus (S. aureus) infection is rapid progression to a serious disease outcome. Changes in immune and inflammatory host responses increase morbidity and complicate efficient therapy. A key player during inflammation is the multifunctional cytokine IL-6. Although increased IL-6 levels have been observed after severe disease upon IV and/or bacterial super-infection, the underlying molecular mechanisms still remain to be elucidated. In the present study, we focused on cellular signalling pathways regulating IL-6 production upon IV/S. aureus super-infection. Additionally, infection with viable bacteria was mimicked by lipoteichoic acid stimulation in this model. Analyses of cellular signalling mechanisms revealed synergistically increased activation of the MAPK p38 as well as enhanced phosphorylation of the MAPKs ERK1/2 and JNK in the presence of super-infecting bacteria. Interestingly, inhibition of MAPK activity indicated a strong dependence of IL-6 expression on p38 and ERK1/2, while the MAPK JNK seems not to be involved. Thus, our results provide new molecular insights into the regulation of IL-6, a marker of severe disease, which might contribute to the lethal synergism of IV and S. aureus.

P38 and JNK Mitogen-Activated Protein Kinases Interact With Chikungunya Virus Non-structural Protein-2 and Regulate TNF Induction During Viral Infection in Macrophages

“…MAPKs are known to regulate TNF production via p-c-jun in other inflammation models (50). Here, it was observed that the expression of p-c-jun is dependent on p-JNK pathway (as SP reduces p-c-jun expression in a dose dependent manner), whereas induction of p-IRF3 is dependent on both MAPKs (p38 and JNK) during CHIKV infection in macrophages.…”

“…Pharmaceutical Inhibitors Specific to p-p38 and p-JNK Reduces CHIKV Induced TNF Production in the Host Macrophages Activation of MAPKs by different pathogens has been shown to induce pro-inflammatory cytokines such as TNF in the host cells (50,54). Since, CHIKV triggers robust TNF production (a key mediator of inflammation) in the host macrophages (31,37), it was interesting to investigate whether any MAPKs are involved in this pathway.…”

“…Although, several other inflammatory cytokines are elevated in RA (rheumatoid arthritis), anti-TNF therapy seems to be promising for the effective treatment against it (79). Since CHIKV induces TNF via p38/JNK MAP kinase pathways and phosphorylation of cjun is reported to be associated with TNF production in other inflammatory model system (50,80), phosphorylation of c-jun in both mock and CHIKV infected macrophages was assessed by Western blot analysis. Surprisingly, the expression of p-cjun was reduced around 1.8-and 4.77-fold in the presence of SP at 5 and 10 µM indicating a plausible role of JNK toward cjun phosphorylation, whereas SB treatment at 1.5 µM did not affect p-c-jun expression significantly.…”

“…There are three major studied ser/thr kinases under the mitogen-activated protein kinase (MAPK) family, such as p38, JNK, and ERK, which are known to regulate multiple cellular pathways such as cell proliferation, activation, inflammation, cytokine and chemokine productions and different pathological conditions (47)(48)(49)(50)(51)(52)(53). In addition, activation of MAPKs by different pathogens and other inflammatory diseases have been reported to induce pro-inflammatory cytokines such as TNF in the host cells (48-51, 53, 54).…”

Short-chain fatty acids increase TNFα-induced inflammation in primary human lung mesenchymal cells through the activation of p38 MAPK

“…To further confirm the involvement of FFAR3 signalling, HLFs were release, we used protein immunoblotting to investigate the activation of signalling pathways. We focussed on five known major signalling pathways (NF-κB, p38 MAPK, AKT, ERK and SAPK/JNK), all of which have been shown to stimulate IL-6 and/or CXCL8 production (22,26,36,41). Phosphorylation of NF-κB was increased 30 minutes after stimulation with TNFα alone (n = 10, p<0.01), but was not increased by concomitant treatment with propionate (p<0.01) ( Figure 4A).…”