Specific inhibitors of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways block inducible nitric oxide synthase and tumor necrosis factor accumulation in murine macrophages stimulated with lipopolysaccharide and interferon-gamma.

Whether p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cascades are required for inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) accumulation in RAW 264.7 murine macrophages exposed to lipopolysaccharide (LPS) plus recombinant interferon-gamma (rIFN-gamma) was investigated. By use of Western blotting for iNOS detection and ELISA for quantitation of TNF secretion, three selective inhibitors of these pathways were tested (the p38 inhibitors SB202190 and SB203580 and the MEK 1,2/ERK inhibitor PD98059). Dose-related inhibition of iNOS production was demonstrated when inhibitors were added 1 h before, simultaneously with, or 1 h after LPS plus rIFN-gamma stimulation. In contrast, inhibition of TNF secretion was observed only when cells were preincubated with these agents. Thus, both the p38 and ERK pathways are involved in the up-regulation of iNOS and TNF production by murine macrophages, and specific inhibitors of these pathways block macrophage iNOS production even when added 1 h after activation of these cells.

[1]  S. Kumar,et al.  SB 203580 inhibits p38 mitogen-activated protein kinase, nitric oxide production, and inducible nitric oxide synthase in bovine cartilage-derived chondrocytes. , 1998, Journal of immunology.

[2]  M. Caivano.  Role of MAP kinase cascades in inducing arginine transporters and nitric oxide synthetase in RAW264 macrophages , 1998, FEBS letters.

[3]  H. Bruining,et al.  Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study. , 1998, Critical care medicine.

[4]  A. Peitzman,et al.  Essential Role of Induced Nitric Oxide in the Initiation of the Inflammatory Response after Hemorrhagic Shock , 1998, The Journal of experimental medicine.

[5]  John C. Lee,et al.  Extracellular Signal-Regulated Kinase and p38 Subgroups of Mitogen-Activated Protein Kinases Regulate Inducible Nitric Oxide Synthase and Tumor Necrosis Factor-α Gene Expression in Endotoxin-Stimulated Primary Glial Cultures , 1998, The Journal of Neuroscience.

[6]  M. Schaller,et al.  Nonselective versus selective inhibition of inducible nitric oxide synthase in experimental endotoxic shock. , 1998, The Journal of infectious diseases.

[7]  C. Nathan,et al.  Perspectives Series : Nitric Oxide and Nitric Oxide Synthases Inducible Nitric Oxide Synthase : What Difference Does It Make ? , 2013 .

[8]  W. Lesslauer,et al.  Blockade of p38 Mitogen-activated Protein Kinase Pathway Inhibits Inducible Nitric-oxide Synthase Expression in Mouse Astrocytes* , 1997, The Journal of Biological Chemistry.

[9]  J. Swantek,et al.  Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-alpha) translation: glucocorticoids inhibit TNF-alpha translation by blocking JNK/SAPK , 1997, Molecular and cellular biology.

[10]  O. Feron,et al.  Nitric oxide synthases: which, where, how, and why? , 1997, Journal of Clinical Investigation.

[11]  F. Fang.  Mechanisms of nitric oxide-related antimicrobial activity , 1997 .

[12]  D E Griswold,et al.  Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. , 1996, The Journal of pharmacology and experimental therapeutics.

[13]  R. Dziarski,et al.  Differential activation of extracellular signal-regulated kinase (ERK) 1, ERK2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinases by bacterial peptidoglycan. , 1996, The Journal of infectious diseases.

[14]  S. L. Orlicek,et al.  Differential effects of tyrosine kinase inhibitors on tumor necrosis factor and nitric oxide production by murine macrophages. , 1996, The Journal of infectious diseases.

[15]  J. Cobb,et al.  Nitric oxide and septic shock. , 1996, JAMA.

[16]  John C. Lee,et al.  Role of CSBP/p38/RK stress response kinase in LPS and cytokine signaling mechanisms , 1996, Journal of leukocyte biology.

[17]  A. Bridges,et al.  A synthetic inhibitor of the mitogen-activated protein kinase cascade. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J. Sjölin,et al.  Plasma levels of cytokines in primary septic shock in humans: correlation with disease severity. , 1995, The Journal of infectious diseases.

[19]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[20]  J. Woodgett,et al.  The stress-activated protein kinase subfamily of c-Jun kinases , 1994, Nature.

[21]  J. Cohen,et al.  Evidence of increased nitric oxide production in patients with the sepsis syndrome. , 1993, Circulatory shock.

[22]  A. DeFranco,et al.  Bacterial lipopolysaccharide induces tyrosine phosphorylation and activation of mitogen-activated protein kinases in macrophages. , 1992, The Journal of biological chemistry.

[23]  Nancy Y. Ip,et al.  ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF , 1991, Cell.

[24]  B. Beutler,et al.  The biology of cachectin/TNF--a primary mediator of the host response. , 1989, Annual review of immunology.