RESUMO
Tuberculosis causes severe immunosuppression thereby ensuring the loss of the host protective immune responses. During Mycobacterium tuberculosis infection, the pathogen modulates TLR-2 receptor down-stream signaling, indicating the possible involvement of TLR-2 in the regulation of the host immune response. Moreover, different PKC isoforms are also involved in the course of infection. Arabinosylated lipoarabinomannan (Ara-LAM) possesses immuno-modulatory properties which induce the pro-inflammatory responses via induction of TLR-2-mediated signaling. Here, we found that pretreatment of M. tuberculosis-infected macrophages with Ara-LAM caused a significant increase in the conventional PKC expression along with their active association with TLR-2. This association activated the TLR-2 -mediated downstream signaling, facilitating the activation of MAP kinase P38. All these events culminated in the up-regulation of proinflammatory response, which was abrogated by treatment with PKC-α and P38 inhibitors. Moreover, pretreatment of macrophages with Ara-LAM abrogated the IL-10 production while restored MHC-II expression in the infected macrophages. This study demonstrates that Ara-LAM confers protection against tuberculosis via TLR-2/PKC signaling crosstalk which is responsible for the induction of host protective immune response against tuberculosis.
Assuntos
Antituberculosos/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/microbiologia , Proteína Quinase C/fisiologia , Tuberculose/imunologia , Animais , Arabinose , Células Cultivadas , Citocinas/biossíntese , Avaliação Pré-Clínica de Medicamentos/métodos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Mediadores da Inflamação/metabolismo , Isoenzimas/biossíntese , Isoenzimas/genética , Macrófagos Peritoneais/enzimologia , Camundongos Endogâmicos C57BL , Viabilidade Microbiana/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/biossíntese , Nitritos/metabolismo , Proteína Quinase C/biossíntese , Proteína Quinase C/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/metabolismo , Tuberculose/enzimologia , Tuberculose/patologia , Regulação para Cima/efeitos dos fármacosRESUMO
In this communication, the ciprofloxacin-trimethoprim (Cp-Tm) combination showed synergistic (Fractional Inhibitory Concentration, FIC index 0.399) and additive (FIC index 0.665-0.83) effects against Vibrio cholerae O1 biotype El Tor serotype Ogawa isolates having Cp MICs 10 microg/ml and Cp 0.66 microg/ml, respectively, following agar dilution checkerboard method. The time-kill study results demonstrated synergy between Cp and Tm against both groups of isolates providing 2.04 log10 (for strain with Cp MIC 0.66 microg/ml) and 3.12 log10 (for strain with Cp MIC 10 microg/ml) decreases in CFU/ml between the combination and its most active compound. Thus, the findings of the present study suggest an introduction of Cp-Tm combination treatment regimen against drug resistant cholera and this in turn will help in combating the drug resistance of V. cholerae O1 biotype El Tor serotype Ogawa.