A Mycoplasma fermentans-derived synthetic lipopeptide induces AP-1 and NF-kappaB activity and cytokine secretion in macrophages via the activation of mitogen-activated protein kinase pathways.

Abstract

Mycoplasma lipoproteins have been demonstrated to stimulate monocytic cells and induce proinflammatory cytokine secretion. In this paper, we show that a synthetic analog of the Mycoplasma fermentans membrane-associated lipopeptide macrophage-activating lipopeptide-2 (MALP-2) induces mRNA synthesis and protein secretion of interleukin-1beta and tumor necrosis factor-alpha in human monocytes/macrophages and the murine macrophage cell line RAW 264.7, whereas the nonlipidated counterpart lacks this effect, underscoring the importance of protein acylation for cell activation. Synthetic MALP-2 (sMALP-2) induced the activation of MAPK family members extracellular signal regulated kinases 1 and 2, c-Jun NH2-terminal kinase, and p38 and induced NF-kappaB and AP-1 transactivation in macrophages. Whereas the specific p38 inhibitor SB203580 abrogated both cytokine synthesis and NF-kappaB and AP-1 transactivation in response to MALP-2, the selective MAPK/extracellular signal-regulated kinase-1 inhibitor PD-98059 decreased interleukin-1beta and tumor necrosis factor-alpha production in response to sMALP-2 without affecting the transactivation of NF-kappaB or AP-1. These results indicate that activation of MAPKs by sMALP-2 is a crucial event leading to the expression of proinflammatory cytokines. Our findings demonstrate that the synthetic analog of MALP-2 reproduces the macrophage stimulation activity found in different fractions of mycoplasmas. Given that MALP-2 has been recently shown to be expressed at the surface of M. fermentans as a molecular entity, sMALP-2 constitutes a valuable surrogate for investigating immunomodulation by these microorganisms and evaluating the role that this activity plays in the development of inflammatory diseases associated with mycoplasma infections.

• Authors: J Garcia, B Lemercier, S Roman-Roman, G Rawadi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 273 Issue 51 Pg. 34391-8 (Dec 18 1998) ISSN: 0021-9258 [Print] United States
• PMID: 9852105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Enzyme Inhibitors
• Flavonoids
• Imidazoles
• Interleukin-1
• Lipopeptides
• Lipopolysaccharides
• Lipoproteins
• NF-kappa B
• Oligopeptides
• Pyridines
• RNA, Messenger
• Recombinant Proteins
• Transcription Factor AP-1
• Tumor Necrosis Factor-alpha
• macrophage stimulatory lipopeptide 2
• Calcium-Calmodulin-Dependent Protein Kinases
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• SB 203580
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• CHO Cells
• Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
• Cell Line
• Cricetinae
• Cytokines (genetics, metabolism)
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Humans
• Imidazoles (pharmacology)
• Interleukin-1 (genetics)
• JNK Mitogen-Activated Protein Kinases
• Lipopeptides
• Lipopolysaccharides (pharmacology)
• Lipoproteins (pharmacology)
• Macrophages (drug effects, physiology)
• Mice
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• Monocytes (drug effects, physiology)
• Mycoplasma fermentans (physiology)
• NF-kappa B (metabolism)
• Oligopeptides (pharmacology)
• Pyridines (pharmacology)
• RNA, Messenger (genetics)
• Recombinant Proteins (biosynthesis)
• Signal Transduction (drug effects)
• Transcription Factor AP-1 (metabolism)
• Transcription, Genetic (drug effects)
• Transfection
• Tumor Necrosis Factor-alpha (genetics)
• p38 Mitogen-Activated Protein Kinases