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.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.
- 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. Garcia, J., Lemercier, B., Roman-Roman, S., Rawadi, G. J. Biol. Chem. (1998) [Pubmed]