Treponema denticola Activates Mitogen-Activated Protein Kinase Signal Pathways through Toll-Like Receptor 2

Abstract

Treponema denticola, a spirochete indigenous to the oral cavity, is associated with host inflammatory responses to anaerobic polymicrobial infections of the root canal, periodontium, and alveolar bone. However, the cellular mechanisms responsible for the recognition of T. denticola by the innate immune system and the underlying cell signaling pathways that regulate the inflammatory response to T. denticola are currently unresolved. In this study, we demonstrate that T. denticola induces innate immune responses via the utilization of Toll-like receptor 2 (TLR2) but not TLR4. Assessment of TLR2/1 and TLR2/6 heterodimers revealed that T. denticola predominantly utilizes TLR2/6 for the induction of cellular responses. Analysis of the mitogenactivated protein kinase (MAPK) signaling pathway in T. denticola-stimulated monocytes identified a prolonged up-regulation of the MAPK extracellular signal-related kinase 1/2 (ERK1/2) and p38, while no discernible increase in phospho-c-Jun N-terminal kinase 1/2 (JNK1/2) levels was observed. With the aid of pharmacological inhibitors selectively targeting ERK1/2 via the mitogen-activated protein kinase/extracellular signal-related kinase 1/2 kinase and p38, we further demonstrate that ERK1/2 and p38 play a major role in T. denticola-mediated pro-and anti-inflammatory cytokine production.

Immune Response and Alveolar Bone Resorption in a Mouse Model ofTreponema denticolaInfection

“…Naïve splenocytes are responsive to T. denticola stimulation in producing a large quantity of IL-10 but not IFN-␥ or IL-13. Ruby et al (23) recently reported that T. denticola can induce the production of IL-10 and a number of proinflammatory cytokines, such as IL-1␤, IL-6, IL-12 p70, and tumor necrosis factor, by macrophages. Nixon et al (21) demonstrated that T. denticola induced production of IL-6 and IL-8, but not MCP-1, by human gingival fibroblasts, while Treponema pectinovorum induced all three cytokines.…”

Virulence Factors of the Oral Spirochete Treponema denticola

“…The LPS tolerance induced by T. denticola components during polymicrobial infection or proliferation may be a general mechanism to evade bacterial clearance. In addition to induction of innate immune responses by TLR2 and TLR4 receptors, T. denticola cells also induce innate immune responses via a TLR2/TLR6 heterodimer with mitogen-activated protein kinases (MAPKs), extracellular regulated protein-serine kinases 1 and 2 (ERK1/2), and p38, playing major roles in the resulting pro-and anti-inflammatory cytokine production (Ruby et al, 2007).…”

Involvement of Toll-Like Receptors 2 and 4 in the Innate Immune Response toTreponema denticolaand Its Outer Sheath Components

“…For instance, TLR4 recognizes gram-negative lipopolysaccharide (LPS), whereas TLR2, as a heterodimer with TLR1 or TLR6, recognizes a diversity of bacterial products, including lipopeptides, peptidoglycans, lipoteichoic acid, and unmodified protein structures (46). It has been reported that TLR2 is critical for human gingival epithelial cells (2) and human macrophages (37) to recognize and respond to T. denticola cells. Macrophage activation through TLR2 leads to upregulation of mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2) and p38 (37), leading to production of both pro-and anti-inflammatory cytokines.…”

“…It has been reported that TLR2 is critical for human gingival epithelial cells (2) and human macrophages (37) to recognize and respond to T. denticola cells. Macrophage activation through TLR2 leads to upregulation of mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2) and p38 (37), leading to production of both pro-and anti-inflammatory cytokines. Nevertheless, the particular T. denticola molecules responsible for TLR-dependent macrophage activation have not been identified.…”