Cholera toxin breakdowns oral tolerance via activation of canonical NF-κB

Area of Science:

• Immunology
• Microbiology
• Molecular Biology

Background:

• Mechanisms of bacterial exotoxin immunogenicity and adjuvanticity are not fully understood.
• Oral tolerance is crucial for preventing unwanted immune responses to food antigens.
• Cholera toxin (CT) is known to affect immune responses, but its precise role in oral tolerance is unclear.

Purpose of the Study:

• To investigate the role of the transcription factor nuclear factor-kappa B (NF-κB) in cholera toxin (CT)-induced alteration of oral tolerance.
• To elucidate the molecular pathways by which CT affects mucosal immunity.

Main Methods:

• Oral administration of CT and ovalbumin (OVA) to mice.
• Assessment of OVA-specific serum antibody responses and CD4(+) T cell proliferation.
• Analysis of NF-κB activation and pro-inflammatory cytokine mRNA expression in mesenteric lymph node (MLN) and Peyer's patch (PP) cells.
• Use of p50 small interfering RNAs (siRNAs) and ADP-ribosylation inhibitors to block NF-κB activation.

Main Results:

• CT feeding abrogated OVA-induced oral tolerance, evidenced by altered antibody responses and T cell proliferation.
• CT activated canonical NF-κB (p50-p65) and induced NF-κB-dependent pro-inflammatory cytokines in MLN and PP cells.
• Pretreatment with p50 siRNAs prevented CT-induced abrogation of oral tolerance.
• ADP-ribosylation inhibitors blocked CT-induced NF-κB activation.

Conclusions:

• CT induces canonical NF-κB activation in intestinal lymphoid cells.
• NF-κB activation plays a critical role in the mucosal immunogenicity and adjuvanticity of CT.
• Targeting NF-κB activation may offer strategies to modulate immune responses to bacterial toxins.