MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress

Abstract

Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-κB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF-κB (BAY-11–7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-κB, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-α, IL-10, IL-2, IL-1β) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF-κB. Inhibition of NF-κB and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-κB/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-κB/p65 phosphorylation. In conclusion, IRB-induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-κB. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-κB independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm.

Hsp90 blockade modulates bullous pemphigoid IgG-induced IL-8 production by keratinocytes

“…Similar to our study, however, inhibition of NFκB by Bay-11-7082 suppressed the upregulation of different proinflammatory cytokines, but also did not compromise the IL-6 response in diaphragm muscle cells exposed to oxidative stress (Sigala et al 2011). One explanation for this and our finding could be that cytokine regulation may be cell type and tissue specific.…”

Bacterial flagellin induces IL-6 expression in human basophils

“…Concordantly, it has been reported that flagellin-induced IL-6 production is regulated by NF-B and AP-1 in chicken heterophils (Kogut et al, 2008) and that CREB activity is also increased by flagellin in primary keratinocytes (Nijnik et al, 2012). It is notable that p38 kinase and ERK are known to be involved in NF-B, AP-1, and CREB activation (Di Giacomo et al, 2009;Sigala et al, 2011;Slomiany and Slomiany, 2013;Tu et al, 2003), which is in line with our results demonstrating that inhibitors for p38 kinase and ERK decreased flagellin-induced IL-6 expression. In addition, NF-B, AP-1, and CREB activation can be also regulated by PKA and PKC (Grassl et al, 1999;Satoh et al, 2004).…”

Heart Failure-Induced Diaphragm Myopathy

“…For instance, ERK 1/2 was stimulated in the diaphragm of rats subjected to increased inspiratory pressure [23] and in skeletal muscle cell culture submitted to hypoxia [52]. In contrast, ERK phosphorylation was decreased in skeletal muscle of rats with sepsis [53].…”

“…In vitro studies have shown that inhibition of this signaling cascade increases slow-twitch fiber-specific proteins and reduces fast-twitch fiber characteristics, inducing the slow muscle fiber phenotype program [20,21]. MAPKs can be modulated by several factors; these include inflammatory cytokines, particularly TNF-α [22,23], and oxidative stress [24], which are increased during HF. JNK is a key protein in mediating TNF-α-induced IGF-I resistance and muscle differentiation suppression [22].…”