Activation of ERK1/2 and TNF-α production are mediated by calcium/calmodulin, and PKA signaling pathways during Mycobacterium bovis infection

Méndez-Samperio, Patricia; Trejo, Artemisa; Miranda, Elena

doi:10.1016/j.jinf.2005.02.027

Cited by 15 publications

(12 citation statements)

References 35 publications

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“…CaMK is a downstream target of Ca 2? and contributes to LPS-induced TNF-a production [32,36,44]. To study the role of CaMK, a downstream effector of Ca 2?…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia

Zhang

et al. 2012

Basic Res Cardiol

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Tumor necrosis factor-α (TNF-α) is a major pro-inflammatory cytokine that causes cardiac dysfunction during sepsis. Na/K-ATPase regulates intracellular Ca(2+), which activates mammalian target of rapamycin (mTOR), a regulator of protein synthesis. The aim of this study was to investigate the role of Na/K-ATPase/mTOR signaling in myocardial TNF-α expression during endotoxemia. Results showed that treatment with LPS decreased Na/K-ATPase activity in the myocardium in vivo and in cultured neonatal cardiomyocytes. Inhibition of Na/K-ATPase by ouabain enhanced LPS-induced myocardial TNF-α protein production, but had no effect on TNF-α mRNA expression. More importantly, ouabain further decreased in vivo cardiac function in endotoxemic mice, which was blocked by etanercept, a TNF-α antagonist. LPS-induced reduction in Na/K-ATPase activity was prevented by inhibition of PI3K, Rac1 and NADPH oxidase using LY294002, a dominant-negative Rac1 adenovirus (Ad-Rac1N17) and apocynin, respectively. To assess the role of Rac1 in Ca(2+) handling, Ca(2+) transients in adult cardiomyocytes from cardiomyocyte-specific Rac1 knockout (Rac1(CKO)) and wild-type (WT) mice were determined. LPS increased intracellular Ca(2+) in WT but not in Rac1(CKO) cardiomyocytes. Furthermore, LPS rapidly increased mTOR phosphorylation in cardiomyocytes, which was blocked by Rac1N17 and an inhibitor of calmodulin-dependent protein kinases (CaMKs) KN93, but enhanced by ouabain. Rapamycin, an inhibitor of mTOR suppressed TNF-α protein levels without any significant effect on its mRNA expression or global protein synthesis. In conclusion, myocardial Na/K-ATPase activity is inhibited during endotoxemia via PI3K/Rac1/NADPH oxidase activation. Inhibition of Na/K-ATPase activates Ca(2+)/CaMK/mTOR signaling, which promotes myocardial TNF-α protein production and cardiac dysfunction during endotoxemia.

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“…CaMK is a downstream target of Ca 2? and contributes to LPS-induced TNF-a production [32,36,44]. To study the role of CaMK, a downstream effector of Ca 2?…”

Section: Discussionmentioning

confidence: 99%

“…Ca 2? /calmodulin-dependent protein kinase (CaMK) activation promotes TNF-a expression in monocytes and macrophages [32,36,44]. To determine if CaMK mediates mTOR activation, cells were pretreated with KN-93, a CaMK inhibitor.…”

Section: Mtor Mediates Lps-induced Tnf-a Protein Expressionmentioning

confidence: 99%

Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia

Zhang

et al. 2012

Basic Res Cardiol

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“…These initial events lead to activation of secondary messengers. Accordingly, some investigations have observed a link between TNF-a and PKC, PKA or PTK [Foster et al, 2000;Chen et al, 2001;Mendez-Samperio et al, 2006]. The TNFR1 receptor has been attributed roles in inducing apoptosis, activating NF-kB, and regulating cell proliferation via MAPK or c-Jun NH 2 -terminal kinases (JNKs)/stressactivated protein kinases (SAPKs) [Beg and Baltimore, 1996;Natoli et al, 1997;Reinhard et al, 1997;Jobin et al, 1999].…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of TNF‐α on the intestinal absorption of galactose

Amador¹,

García-Herrera²,

Marca³

et al. 2006

J of Cellular Biochemistry

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Sepsis is a systemic response to infection in which toxins, such as bacterial lipopolysaccharide (LPS), stimulate the production of inflammatory mediators like the cytokine tumor necrosis factor alpha (TNF-alpha). Previous studies from our laboratory have revealed that LPS inhibits the intestinal absorption of L-leucine and D-fructose in rabbit when it was intravenously administered, and that TNF-alpha seems to mediate this effect on amino acid absorption. To extend this work, the present study was designed to evaluate the possible effect of TNF-alpha on D-galactose intestinal absorption, identify the intracellular mechanisms involved and establish whether this cytokine mediates possible LPS effects. Our findings indicate that TNF-alpha decreases D-galactose absorption both in rabbit intestinal tissue preparations and brush-border membrane vesicles. Western blot analysis revealed reduced amounts of the Na+/glucose cotransporter (SGLT1) protein in the plasma membrane attributable to the cytokine. On the contrary, TNF-alpha increased SGLT1 mRNA levels. Specific inhibitors of the secondary messengers PKC, PKA, the MAP kinases p38 MAP, JNK, MEK1/2 as well as the proteasome, diminished the TNF-alpha-evoked inhibitory effect. LPS inhibition of the uptake of the sugar was blocked by a TNF-alpha antagonist. In conclusion, TNF-alpha inhibits D-galactose intestinal absorption by decreasing the number of SGLT1 molecules at the enterocyte plasma membrane through a mechanism in which several protein-like kinases are involved.

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“…Indeed, calcium channel blockade is associated with decreased TNF-α levels in a rat septic shock model [13]. Recently, a correlation between calcium levels, ERK phosphorylation and TNF-α expression was established in mononuclear cells following Mycobacterium bovis infection [14]. However, the upstream regulators of calcium-dependent TNF-α expression have not been investigated and the role of calcium in regulating ERK phosphorylation and TNF-α expression in cardiomyocytes is unclear.…”

Section: Introductionmentioning

confidence: 99%

Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes

Geoghegan-Morphet

Burger

et al. 2007

Cardiovascular Research

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Activation of ERK1/2 and TNF-α production are mediated by calcium/calmodulin, and PKA signaling pathways during Mycobacterium bovis infection

Cited by 15 publications

References 35 publications

Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia

Inhibition of Na/K-ATPase promotes myocardial tumor necrosis factor-alpha protein expression and cardiac dysfunction via calcium/mTOR signaling in endotoxemia

Inhibitory effect of TNF‐α on the intestinal absorption of galactose

Role of neuronal nitric oxide synthase in lipopolysaccharide-induced tumor necrosis factor-alpha expression in neonatal mouse cardiomyocytes

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