Campylobacter jejuni Drives MyD88-Independent Interleukin-6 Secretion via Toll-Like Receptor 2

Abstract

Gastrointestinal disease caused by Campylobacter jejuni is characterized by localized inflammation and the destruction of the epithelial cell barrier that forms host innate protection against pathogens. This can lead to an imbalance in fluid transport across the gastrointestinal tract, resulting in severe diarrhea. The mechanisms of host cell receptor recognition of C. jejuni and downstream immune signaling pathways leading to this inflammatory disease, however, remain unclear. The aim of this study was to analyze the mechanisms involved in C. jejuni induction of the acute-phase inflammatory response regulator interleukin-6 (IL-6). Polarized intestinal epithelial Caco-2 monolayers responded to infections with Salmonella enterica serovar Typhimurium and eight isolates of C. jejuni by an increase in levels of expression and secretion of IL-6. No such IL-6 response, however, was produced upon infection with the human commensal organism Lactobacillus rhamnosus GG. The IL-6 signaling pathway was further characterized using short interfering RNA complexes to block gene expression. The inhibition of myeloid differentiation primary response protein 88 (MyD88) expression in this manner did not affect C. jejuni-induced IL-6 secretion, suggesting a MyD88-independent route to IL-6 signal transduction in C. jejuni-infected human epithelial cells. However, a significant reduction in levels of IL-6 was evident in the absence of Toll-like receptor 2 (TLR-2) expression, implying a requirement for TLR-2 in C. jejuni recognition. Caco-2 cells were also treated with heat-inactivated and purified membrane components of C. jejuni to isolate the factor responsible for triggering IL-6 signaling. The results demonstrate that C. jejuni surface polysaccharides induce IL-6 secretion from intestinal epithelial cells via TLR-2 in a MyD88-independent manner.

Comparative Kinetics ofEscherichia coli- andStaphylococcus aureus-Specific Activation of Key Immune Pathways in Mammary Epithelial Cells Demonstrates ThatS. aureusElicits a Delayed Response Dominated by Interleukin-6 (IL-6) but Not by IL-1A or Tumor Necrosis Factor Alpha

“…We found that the expression of either construct in MAC-T cells does not affect the induction of IL-6 synthesis in response to an E. coli challenge. A MyD88-independent activation of IFN-␤ and IL-6 expression was previously observed for macrophages (28) and intestinal epithelial cells (12). Our present results for the MyD88-independent induction of IL-6 expression with the previously reported S. aureus-mediated prevention of NF-B activation in pbMEC (58) collectively suggest that S. aureus may indeed subvert the MyD88-dependent route of TLR signaling in MEC.…”

The Campylobacter jejuni Transcriptional Regulator Cj1556 Plays a Role in the Oxidative and Aerobic Stress Response and Is Important for Bacterial SurvivalIn Vivo

“…In this study, there was no significant difference in the levels of IL-8 induction by the Cj1556 mutant and the 11168H wildtype strain; however, a significant reduction in the level of IL-6 induction by the Cj1556 mutant compared to the 11168H wildtype strain was observed. IL-8 acts as a chemoattractant, allowing the recruitment of lymphocytes and neutrophils (32,62), whereas IL-6 is believed to be important for epithelial cell integrity (27). It is possible that less IL-6 was induced when T84 cells were cocultured with the Cj1556 mutant than with the 11168H wild-type strain due to the decreased survival characteristic of the Cj1556 mutant strain.…”

Activation of Human and Chicken Toll-Like Receptors by Campylobacter spp

“…jejuni initiates both MyD88 and TRIF-dependent immune responses through the activation of human TLR2 and TLR4 (17,43), whereas stimulation of human TLR9 only resulted in low levels of IL-8 secretion (12). Furthermore, C. jejuni is unable to activate human TLR5 (3,58).…”