MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing

The role of oxidative stress

Ioanna Sigala, Panayiotis Zacharatos, Dimitris Toumpanakis, Tatiana Michailidou, Olga Noussia, Stamatios Theocharis, Charis Roussos, Andreas Papapetropoulos, Theodoros Vassilakopoulos

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 twoway 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume300
Issue number5
DOIs
StatePublished - May 1 2011
Externally publishedYes

Fingerprint

Diaphragm
Respiration
Oxidative Stress
Cytokines
Up-Regulation
Interleukin-6
p38 Mitogen-Activated Protein Kinases
Cysteine
Phosphorylation
Interleukin-1
Interleukin-10
Interleukin-2
Wistar Rats

Keywords

  • Exercise
  • Inflammation
  • Respiratory muscles
  • Skeletal muscle

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing : The role of oxidative stress. / Sigala, Ioanna; Zacharatos, Panayiotis; Toumpanakis, Dimitris; Michailidou, Tatiana; Noussia, Olga; Theocharis, Stamatios; Roussos, Charis; Papapetropoulos, Andreas; Vassilakopoulos, Theodoros.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 300, No. 5, 01.05.2011.

Research output: Contribution to journalArticle

Sigala, Ioanna ; Zacharatos, Panayiotis ; Toumpanakis, Dimitris ; Michailidou, Tatiana ; Noussia, Olga ; Theocharis, Stamatios ; Roussos, Charis ; Papapetropoulos, Andreas ; Vassilakopoulos, Theodoros. / MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing : The role of oxidative stress. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2011 ; Vol. 300, No. 5.
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AU - Michailidou, Tatiana

AU - Noussia, Olga

AU - Theocharis, Stamatios

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AU - Vassilakopoulos, Theodoros

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AB - 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 twoway 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.

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