Treponema pallidum flagellins elicit proinflammatory cytokines from human monocytes via TLR5 signaling pathway

Abstract

The tissue damage caused by syphilis infection may be associated with inflammation. However, the virulence factors of Treponema pallidum are still unclear, nor are the molecular mechanisms for leading to the productions of proinflammatory cytokines. Flagellin, a classic pathogen-associated molecular pattern (PAMP), is a potent immunogen that induces inflammation. In the present study, we have demonstrated that stimulations of human monocytes with Treponema pallidum FlaB1, FlaB2, and FlaB3 result in the up regulation of interleukin (IL)-6 and IL-8. Moreover, silencing of the Toll-like receptor 5 (TLR5) gene by using small interfering RNA was found to abrogate the T. pallidum flagellins-induced IL-6 and IL-8 expressions. Similarly, transfection with the dominant negative plasmid encoding MyD88 (pDeNy-hMyD88) was also giving rise to the down regulation of IL-6 and IL-8. We further investigated the relative contributions of mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling to transcriptions and translations of IL-6 and IL-8. Western Blot and immuno fluorescence experiments revealed that flagellins-mediated IL-6 and IL-8 expressions are heavily dependent on ERK, p38, and NF-κB. In addition, inhibitions of p38 kinase, ERK, and NF-κB were found to attenuate the productions of IL-6 and IL-8. Taken together, our results indicate that T. pallidum flagellins can upregulate IL-6 and IL-8 generations via TLR5 and MAPK/NF-κB signaling pathways in THP-1 cells, which will improve our understanding of the pathogenesis of T. pallidum.

Keywords: Flagellin; Human monocytes; Inflammation; TLR5 signaling; Treponema pallidum.