Lactobacilli and streptococci activate NF-kappa B and STAT signaling pathways in human macrophages

Gram-positive bacteria induce the production of several cytokines in human leukocytes, The molecular mechanisms involved in Gram-positive bacteria-ind uced cytokine production have been poorly characterized. In this work we de monstrate that both nonpathogenic Lactobacillus rhamnosus GG and pathogenic Streptococcus pyogenes (group A streptococci) induce NF-kappa B and STAT D NA-binding activity in human primary macrophages as analyzed by EMSA, NF-ka ppa B activation was rapid and was not inhibited by a protein synthesis inh ibitor cycloheximide, suggesting that these bacteria could directly activat e NF-kappa B. STAT1, STAT3, and IFN regulatory factor-1 DNA binding was ind uced by both bacteria with delayed kinetics compared with NF-kappa B. In ad dition, streptococci induced the formation of IFN-alpha-specific transcript ion factor complex and IFN-stimulated gene factor-3 (ISGF3), STAT1 and STAT 3 activation and ISGF3 complex formation were inhibited by cycloheximide or by neutralization with IFN-alpha/beta-specific Abs, Streptococci were more potent than lactobacilli in inducing STAT1, ISGF3, and IFN regulatory fact or-1 DNA binding. Accordingly, only streptococci induced IFN-alpha producti on, The activation of the IFN-alpha signaling pathway by streptococci could play a role in the pathogenesis of these bacteria, These results indicate that extracellular Gram-positive bacteria activate transcription factors in volved in cytokine signaling by two mechanisms: directly, leading to NF-kap pa B activation, and indirectly via cytokines, leading to STAT activation.