title: Requirement of mitogen-activated protein kinases and I kappa B phosphorylation for induction of proinflammatory cytokines synthesis by macrophages indicates functional similarity of receptors triggered by glycosylphosphatidylinositol anchors from parasitic protozoa and bacterial lipopolysaccharide.
abstract: In the present study, we evaluated the ability of GPI-anchored mucin-like glycoproteins purified from Trypanosoma cruzi trypomastigotes (tGPI-mucin) to trigger phosphorylation of different mitogen-activated protein kinases (MAPKs) and related transcription factors in inflammatory macrophages. Kinetic experiments show that the peak of extracellular signal-related kinase (ERK)-1/ERK-2, stress-activated protein kinase (SAPK) kinase-1/mitogen-activated protein kinase (MAPK) kinase-4, and p38/SAPK-2, phosphorylation occurs between 15 and 30 min after macrophage stimulation with tGPI-mucin or GPI anchors highly purified from tGPI-mucins (tGPI). The use of the specific inhibitors of ERK-1/ERK-2 (PD 98059) and p38/SAPK-2 (SB 203580) phosphorylation also indicates the role of MAPKs, with possible involvement of cAMP response element binding protein, in triggering TNF-alpha and IL-12 synthesis by IFN-gamma-primed-macrophages exposed to tGPI or tGPI-mucin. In addition, tGPI-mucin and tGPI were able to induce phosphorylation of I kappa B, and the use of SN50 peptide, an inhibitor of NF-kappa B translocation, resulted in 70% of TNF-alpha synthesis by macrophages exposed to tGPI-mucin. Finally, the similarity of patterns of MAPK and I kappa B phosphorylation, the concentration of drugs required to inhibit cytokine synthesis, as well as cross-tolerization exhibited by macrophages exposed to tGPI, tGPI-mucin, or bacterial LPS, suggest that receptors with the same functional properties are triggered by these different microbial glycoconjugates.
authors.affiliation: René Rachou Research Center-Fundaçao Oswaldo Cruz, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: C
authors.initials: C
authors.lastname: Ropert
authors.forename: I C
authors.initials: IC
authors.lastname: Almeida
authors.forename: M
authors.initials: M
authors.lastname: Closel
authors.forename: L R
authors.initials: LR
authors.lastname: Travassos
authors.forename: M A
authors.initials: MA
authors.lastname: Ferguson
authors.forename: P
authors.initials: P
authors.lastname: Cohen
authors.forename: R T
authors.initials: RT
authors.lastname: Gazzinelli
mesh_terms: D051698:Activating Transcription Factor 2; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects; D007249:Inflammation / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009077:Mucins / Q000276:immunology; D016328:NF-kappa B / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D015800:Protozoan Proteins / Q000276:immunology; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017261:Glycosylphosphatidylinositols; D020672:I-kappa B Proteins; D007093:Imidazoles; D008070:Lipopolysaccharides; D009077:Mucins; D016328:NF-kappa B; D015800:Protozoan Proteins; D011725:Pyridines; D011956:Receptors, Cell Surface; C412510:TgPI protein, Toxoplasma gondii; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C033639:glycolipid receptor; D018664:Interleukin-12; D009569:Nitric Oxide; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one