title: p38 MAP kinase regulates TNF alpha-, IL-1 alpha- and PAF-induced RANTES and GM-CSF production by human bronchial epithelial cells.
abstract: BACKGROUND
  RANTES and granulocyte macrophage-colony stimulating factor (GM-CSF) play an important role in the production of allergic inflammation of the airway through their chemotactic activity for eosinophils. Recent studies have indicated that p38 mitogen-activated protein (MAP) kinase regulates cytokine expression in various cells; however, the role of p38 MAP kinase in RANTES and GM-CSF production in human bronchial epithelial cells (BECs) has not yet been determined.
  
  
  OBJECTIVE
  In the present study, we examined serine phosphorylation of MKK3 and MKK6 which is the upstream regulator of p38 MAP kinase and p38 MAP kinase activation in tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha and platelet-activating factor (PAF)-stimulated BECs and the effect of SB 203580 as the specific inhibitor for p38 MAP kinase activity on RANTES and GM-CSF expression in order to clarify the intracellular signal regulating RANTES and GM-CSF production by human BECs.
  
  
  RESULTS
  The results showed that TNF alpha, IL-1 alpha and PAF induced serine phosphorylation of MKK3 and MKK6, and p38 MAP kinase activation in BECs. SB 203580 inhibited p38 MAP kinase activity and RANTES and GM-CSF production by TNF alpha-, IL-1 alpha- or PAF-stimulated human BECs.
  
  
  CONCLUSIONS
  These results indicate that p38 MAP kinase plays an important role in TNF alpha-, IL-1 alpha- or PAF-activated signalling pathway which regulates RANTES and GM-CSF production by BECs and that the specific inhibitor for p38 MAP kinase activity might be useful for the treatment of allergic inflammation of the airway.
authors.affiliation: First Department of Internal Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Gon
authors.forename: S
authors.initials: S
authors.lastname: Maruoka
authors.forename: K
authors.initials: K
authors.lastname: Kujime
authors.forename: S
authors.initials: S
authors.lastname: Hayashi
authors.forename: I
authors.initials: I
authors.lastname: Takeshita
authors.forename: T
authors.initials: T
authors.lastname: Horie
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D002461:Cell Line, Transformed; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018946:Chemokine CCL5; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D010972:Platelet Activating Factor; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580