title: Interleukin-1beta induction of mitogen-activated protein kinases in human mesangial cells. Role of oxidation.
abstract: Interleukin-1beta (IL-1beta) significantly influences renal cellular function through the induction of several gene products. The molecular mechanisms involved in gene regulation by IL-1beta are poorly understood; however, the appearance of novel tyrosine phosphoproteins in IL-1beta-treated cells suggests that IL-1beta may function through tyrosine phosphoprotein intermediates. The mitogen-activated protein (MAP) kinases are tyrosine phosphoproteins that could potentially mediate the effects of IL-1beta. Protein tyrosine phosphorylation following IL-1beta treatment may be dependent on redox changes since the IL-1beta receptor is not a protein-tyrosine kinase and oxidation has been shown to induce tyrosine phosphorylation. In this report we demonstrate that conditioning human glomerular mesangial cells with IL-1beta results in the tyrosine phosphorylation and activation of two members of the MAP kinase family, extracellular signal-regulated protein kinase 2 (ERK2) and p54 Jun-NH2-terminal kinase (JNK). This effect of IL-1beta is abrogated by pretreating cells with the antioxidants N-acetyl-L-cysteine or dithiothreitol. Furthermore, the effects of IL-1beta on ERK and JNK activation are reproduced by treating mesangial cells with membrane-permeable oxidants. IL-1beta and oxidants also cause phosphorylation and activation of the upstream ERK regulatory element MAP kinase kinase. Interestingly, IL-1beta, but not exogenous oxidants, causes phosphorylation of the upstream JNK activator, JNK kinase. These data indicate that IL-1beta activates ERK2 through an oxidation-dependent pathway. Exogenous oxidants and IL-1beta activate JNK through different upstream mechanisms; however, antioxidant inhibition of JNK activation indicates that endogenous oxidants may play a role in IL-1beta-induced JNK activation. Thus IL-1beta may affect mesangial cell function by activating MAP kinases, which can then regulate gene transcription. Furthermore, reactive oxygen species released during inflammatory glomerular injury may also affect mesangial function through a MAP kinase signal.
authors.affiliation: Department of Medicine, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Wilmer
authors.forename: L C
authors.initials: LC
authors.lastname: Tan
authors.forename: J A
authors.initials: JA
authors.lastname: Dickerson
authors.forename: M
authors.initials: M
authors.lastname: Danne
authors.forename: B H
authors.initials: BH
authors.lastname: Rovin
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis* / Q000302:isolation & purification / Q000378:metabolism; D002478:Cells, Cultured; D003958:Diamide / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004789:Enzyme Activation; D004790:Enzyme Induction / Q000187:drug effects; D005920:Glomerular Mesangium / Q000201:enzymology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis / Q000302:isolation & purification; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D010084:Oxidation-Reduction; D010750:Phosphoproteins / Q000096:biosynthesis / Q000302:isolation & purification; D019000:Phosphotyrosine / Q000032:analysis; D011494:Protein Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D007375:Interleukin-1; D007527:Isoenzymes; D010750:Phosphoproteins; D011994:Recombinant Proteins; D003958:Diamide; D019000:Phosphotyrosine; D006861:Hydrogen Peroxide; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D004229:Dithiothreitol; D000111:Acetylcysteine