Abstract
Toll-like receptors (TLRs) 2 and 4 play critical roles in intestinal inflammation caused by Fusobacterium nucleatum (F. nucleatum) infection, but the role of TLR2/TLR4 in regulation of proinflammatory cytokines remains unknown. In this study, through microarray analysis and qRT-PCR, we showed that TLR2/TLR4 are involved in the F. nucleatum-induced inflammatory signaling pathway in Caco-2 cells, C57BL/6 mice and human clinical specimens. In TLR2-/- and TLR4-/- mice, F. nucleatum infection resulted in increased colonization of the bacteria and production of the proinflammatory cytokines IL-8, IL-1β and TNF-α. In addition, the ratio of Foxp3+ CD4+ T cells in the total CD4+ T cells in TLR2-/- and TLR4-/- mice was less than that in wild-type mice, and the ratio in hybrid mice was more than that in knockout mice, which suggested that TLR2/TLR4 mediated the number of Tregs. Furthermore, it was observed that inflammatory cytokine levels were reduced in TLR2-/- mice after Treg transfer. Thus, these data indicate that TLR2/TLR4 regulate F. nucleatum-induced inflammatory cytokines through Tregs in vivo.
Highlights
Fusobacterium nucleatum (F. nucleatum), an anaerobic gram-negative bacterium, is normally prevalent in the oral cavity
In the course of the study, via an Affymetrix microarray analysis in Caco-2 cells infected with F. nucleatum, we observed that the Toll-like receptor signaling pathway may participate in F. nucleatuminduced inflammation (Fig 1A)
There was an increase in the RNA expression of TLR2 and TLR4 in cells or mice infected with F. nucleatum compared to controls, while F. nucleatum infection had no significant effect on the RNA expression of TLR1, TLR5 and TLR6 (Fig 1B and 1C), which suggested that TLR2 and TLR4 may be involved in F. nucleatum-induced inflammation
Summary
Fusobacterium nucleatum (F. nucleatum), an anaerobic gram-negative bacterium, is normally prevalent in the oral cavity. This bacteria is the main cause of periodontal disease, and it is implicated in abscesses, inflammatory bowel disease (IBD), and colon cancer [1]. An accumulating number of investigations have found that F. nucleatum infection can lead to an inappropriate inflammatory response in intestinal epithelial cells [3], and F. nucleatum is significantly concentrated in inflammatory bowel tissue in patients with IBD [4,5,6]. TLRs are mainly expressed in the plasma membrane and the membrane of intracellular vesicles.
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