Ouabain Suppresses IL-6/STAT3 Signaling and Promotes Cytokine Secretion in Cultured Skeletal Muscle Cells

被引:20
|
作者
Pirkmajer, Sergej [1 ]
Bezjak, Katja [1 ]
Matkovic, Urska [1 ]
Dolinar, Klemen [1 ]
Jiang, Lake Q. [2 ]
Mis, Katarina [1 ]
Gros, Katarina [1 ]
Milovanova, Kseniya [3 ]
Pirkmajer, Katja Perdan [4 ,5 ]
Mars, Tomaz [1 ]
Kapilevich, Leonid [3 ,6 ]
Chibalin, Alexander V. [2 ]
机构
[1] Univ Ljubljana, Inst Pathophysiol, Fac Med, Ljubljana, Slovenia
[2] Karolinska Inst, Dept Mol Med & Surg, Integrat Physiol, Stockholm, Sweden
[3] Natl Res Tomsk State Univ, Dept Sports & Hlth Tourism Sports Physiol & Med, Tomsk, Russia
[4] Univ Med Ctr Ljubljana, Dept Rheumatol, Ljubljana, Slovenia
[5] Univ Ljubljana, Fac Med, Dept Internal Med, Ljubljana, Slovenia
[6] Siberian State Med Univ, Cent Sci Lab, Tomsk, Russia
来源
FRONTIERS IN PHYSIOLOGY | 2020年 / 11卷
基金
瑞典研究理事会; 俄罗斯科学基金会;
关键词
Ouabain; marinobufagenin; Na; K-ATPase; cytokines; skeletal muscle; IL-6; NA+-K+-ATPASE; ENDOGENOUS CARDIOTONIC STEROIDS; BOVINE ADRENOCORTICAL-CELLS; NA; K-ATPASE ALPHA-SUBUNIT; GLYCOSIDE BINDING-SITE; ACTIVE-TRANSPORT; ADENOSINE-TRIPHOSPHATASE; PHYSICAL-EXERCISE; CARDIAC-GLYCOSIDES; BLOOD-PRESSURE;
D O I
10.3389/fphys.2020.566584
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
The cardiotonic steroids (CTS), such as ouabain and marinobufagenin, are thought to be adrenocortical hormones secreted during exercise and the stress response. The catalytic alpha-subunit of Na,K-ATPase (NKA) is a CTS receptor, whose largest pool is located in skeletal muscles, indicating that muscles are a major target for CTS. Skeletal muscles contribute to adaptations to exercise by secreting interleukin-6 (IL-6) and plethora of other cytokines, which exert paracrine and endocrine effects in muscles and non-muscle tissues. Here, we determined whether ouabain, a prototypical CTS, modulates IL-6 signaling and secretion in the cultured human skeletal muscle cells. Ouabain (2.5-50 nM) suppressed the abundance of STAT3, a key transcription factor downstream of the IL-6 receptor, as well as its basal and IL-6-stimulated phosphorylation. Conversely, ouabain (50 nM) increased the phosphorylation of ERK1/2, Akt, p70S6K, and S6 ribosomal protein, indicating activation of the ERK1/2 and the Akt-mTOR pathways. Proteasome inhibitor MG-132 blocked the ouabain-induced suppression of the total STAT3, but did not prevent the dephosphorylation of STAT3. Ouabain (50 nM) suppressed hypoxia-inducible factor-1 alpha (HIF-1 alpha), a modulator of STAT3 signaling, but gene silencing of HIF-1 alpha and/or its partner protein HIF-1 beta did not mimic effects of ouabain on the phosphorylation of STAT3. Ouabain (50 nM) failed to suppress the phosphorylation of STAT3 and HIF-1 alpha in rat L6 skeletal muscle cells, which express the ouabain-resistant alpha 1-subunit of NKA. We also found that ouabain (100 nM) promoted the secretion of IL-6, IL-8, GM-CSF, and TNF-alpha from the skeletal muscle cells of healthy subjects, and the secretion of GM-CSF from cells of subjects with the type 2 diabetes. Marinobufagenin (10 nM), another important CTS, did not alter the secretion of these cytokines. In conclusion, our study shows that ouabain suppresses the IL-6 signaling via STAT3, but promotes the secretion of IL-6 and other cytokines, which might represent a negative feedback in the IL-6/STAT3 pathway. Collectively, our results implicate a role for CTS and NKA in regulation of the IL-6 signaling and secretion in skeletal muscle.
引用
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页数:23
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