Mycoplasma fermentans lipoproteins (LAMPf) are capable of activating macrophages and inducing the secretion of proinflammatory cytokines. We have recently reported that mitogen-activated protein kinase (MAPK) pathways and NF-kappaB and activated protein 1 (AP-1) play a crucial role in the activation induced by this bacterial compound. To further elucidate the mechanisms by which LAMPf mediate the activation of macrophages, we assessed the effects of inhibiting small G proteins Rac, Cdc42, and Rho. The Rho-specific inhibitor C3 enzyme completely abolished the secretion of tumor necrosis factor alpha by macrophages stimulated with LAMPf and also inhibited the activation of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 kinase. In addition, we have shown that LAMPf stimulate Cdc42 and that inhibition of Cdc42 or Rac by dominant negative mutants abrogates LAMPf-mediated activation of JNK and transactivation of NF-kappaB and AP-1 in the murine macrophage cell line RAW 264.7. These results indicate that small G proteins Rho, Cdc42, and Rac are involved in the cascade of events leading to the macrophage activation by mycoplasma lipoproteins.
"PARP-1 is known to be activated by DNA breaks; however recently, it was reported that PARP-1 can be activated by phosphorylated ERK2 in the absence of stress conditions or DNA damage . In recent studies Mycoplasma was demonstrated to be capable of activating various MAPKs, such as SAPK/JNK, p38, NF-kB, AP-1, and ERK 1/2 in response to Mycoplasma-derived membrane lipoproteins , –. Thus it is important to investigate the possibility that the cellular Topo I and the efficacy of CPTs as anti-cancer agents might be affected by Mycoplasma infection. "
[Show abstract][Hide abstract] ABSTRACT: To understand the effects of the interaction between Mycoplasma and cells on the host cellular function, it is important to elucidate the influences of infection of cells with Mycoplasma on nuclear enzymes such as DNA Topoisomerase type I (Topo I). Human Topo I participates in DNA transaction processes and is the target of anti-cancer drugs, the camptothecins (CPTs). Here we investigated the mechanism by which infection of human tumor cells with Mycoplasma fermentans affects the activity and expression of cellular Topo I, and the anti-cancer efficacy of CPT. Human cancer cells were infected or treated with live or sonicated M. fermentans and the activity and expression of Topo I was determined. M. fermentans significantly reduced (by 80%) Topo I activity in the infected/treated tumor cells without affecting the level of Topo I protein. We demonstrate that this reduction in enzyme activity resulted from ADP-ribosylation of the Topo I protein by Poly-ADP-ribose polymerase (PARP-1). In addition, pERK was activated as a result of the induction of the MAPK signal transduction pathway by M. fermentans. Since PARP-1 was shown to be activated by pERK, we concluded that M. fermentans modified the cellular Topo I activity by activation of PARP-I via the induction of the MAPK signal transduction pathway. Moreover, the infection of tumor cells with M. fermentans diminished the inhibitory effect of CPT. The results of this study suggest that modification of Topo I activity by M. fermentans may alter cellular gene expression and the response of tumor cells to Topo I inhibitors, influencing the anti-cancer capacity of Topo I antagonists.
PLoS ONE 08/2013; 8(8):e72377. DOI:10.1371/journal.pone.0072377 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mycoplasmas are the smallest free-living self-replicating bacteria - having diameters of 200 to 800 nm - widely distributed in animals and plants. Mycoplasma fermentans is a human pathogen suspected to be involved in the progression of autoimmune diseases. Although pathogenesis mechanisms of M. fermentans are currently poorly understood, the role of these microorganisms as immunomodulatory agents is well established. In the present paper, we will review and discuss recent breakthroughs in the field.
Microbes and Infection 08/2000; 2(8):955-64. DOI:10.1016/S1286-4579(00)00395-6 · 2.86 Impact Factor
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