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p38 mitogen-activated protein kinase mediates tumor necrosis factor-alpha-induced apoptosis in rat fetal brown

A Valladares1, A M Alvarez, J J Ventura

  • 1Departamento de Bioquímica y Biología Molecular II, Instituto de Bioquímica, Centro Mixto del Consejo Superior de Investigaciones Cientificas y de la Universidad Complutense de Madrid, Spain.

Endocrinology
|December 7, 2000
PubMed

Insights

Tumor necrosis factor-alpha (TNFalpha) triggers apoptosis and cell cycle arrest in brown adipocytes via p38MAPK signaling. Extracellular regulated kinases (ERKs) have opposing effects, while c-Jun N-terminal kinases (JNKs) are not involved.

Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Biochemistry

Background:

  • Tumor necrosis factor-alpha (TNFalpha) is a key cytokine involved in inflammation and apoptosis.
  • Mitogen-activated protein kinases (MAPKs) are crucial signaling pathways regulating cellular responses.
  • The specific roles of MAPK superfamily members in TNFalpha-induced adipocyte apoptosis remain incompletely understood.

Purpose of the Study:

  • To elucidate the involvement of MAPK signaling pathways in TNFalpha-induced apoptosis and cell cycle arrest in rat fetal brown adipocytes.
  • To identify downstream effectors mediating TNFalpha's actions within these pathways.

Main Methods:

  • Primary rat fetal brown adipocytes were treated with TNFalpha.
  • Specific MAPK inhibitors (SB203580, SB202190, MEK1 inhibitor) and dominant-negative constructs were used.
  • Apoptosis, cell cycle arrest, and the activation/phosphorylation of key signaling molecules (p38MAPK, ERK1/2, c-Jun, ATF-1, NF-kappaB, JNK) were assessed.

Main Results:

  • TNFalpha activated both p38MAPK and ERK1/2 pathways.
  • p38MAPK inhibition significantly reduced TNFalpha-induced apoptosis and cell cycle arrest.
  • ERK inhibition potentiated TNFalpha-induced apoptosis and affected cell cycle arrest markers.
  • c-Jun and ATF-1 were identified as downstream effectors, with differential regulation by p38MAPK and ERKs.
  • JNK activation by TNFalpha did not influence apoptosis.

Conclusions:

  • p38MAPK is a critical mediator of TNFalpha-induced apoptosis and cell cycle arrest in brown adipocytes.
  • ERK signaling opposes these effects, suggesting a complex regulatory balance.
  • Downstream targets like c-Jun and ATF-1 are differentially regulated, highlighting pathway crosstalk.
  • JNK signaling is not involved in TNFalpha-mediated adipocyte apoptosis.

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