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Thrombin induces inducible nitric oxide synthase expression via the MAPK, MSK1, and NF-κB signaling pathways in

Chen-Chun Lin1, Chung-Huang Shih, You-Lan Yang

  • 1Department of Chest Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.

European Journal of Pharmacology
|October 19, 2011
PubMed

Insights

Thrombin increases inducible nitric oxide synthase (iNOS) in macrophages via MAPK, MSK1, and NF-κB pathways. Inhibiting these pathways, including p38 MAPK, MEK, JNK, MSK1, and NF-κB, reduces iNOS expression, revealing key regulatory mechanisms.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Inducible nitric oxide synthase (iNOS) plays a crucial role in inflammatory responses within macrophages.
  • Thrombin is a known activator of various cellular signaling cascades.
  • Understanding the molecular mechanisms regulating iNOS expression is vital for addressing inflammatory conditions.

Purpose of the Study:

  • To elucidate the specific roles of mitogen-activated protein kinase (MAPK), mitogen stress-activated protein kinase 1 (MSK1), and nuclear factor-κB (NF-κB) signaling pathways in thrombin-induced iNOS expression.
  • To investigate the upstream regulators and downstream effectors involved in this process within alveolar macrophages.

Main Methods:

  • Utilized NR8383 alveolar macrophage cell line.
  • Administered thrombin and specific pathway inhibitors (SB203580, PD98059, SP600125, Ro 31-8220, PDTC) and MSK1 siRNA.
  • Assessed iNOS expression, MAPK, MSK1, and NF-κB pathway activation through phosphorylation and luciferase activity assays.

Main Results:

  • Thrombin upregulated iNOS expression in a dose- and time-dependent manner.
  • Inhibitors of p38 MAPK, MEK, JNK, MSK1, and NF-κB significantly reduced thrombin-induced iNOS expression.
  • Thrombin activated p38 MAPK, ERK, JNK, MSK1, and NF-κB signaling, with MSK1 and NF-κB activation being downstream of MAPK pathways.

Conclusions:

  • MAPK, MSK1, and NF-κB signaling pathways are critical mediators of thrombin-induced iNOS expression in alveolar macrophages.
  • This study identifies a complex signaling network involving these pathways in regulating iNOS production.
  • Findings provide insights into the molecular basis of thrombin-mediated inflammation in macrophages.

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