Differential Activity of Il-12 and Il-23 in Mucosal and Systemic Innate Immune Pathology

Aim:

Inflammatory bowel disease is a complex disease of the gastrointestinal tract involving local activation of the innate and adaptive immune system. The CD40-CD154 pathway plays an important role in the cross-talk between myeloid cells and T cells that drives the inflammatory response in IBD.

Methods:

Here we have developed a model system in which CD40L expressing activated T cells are replaced with an agonist anti-CD40 mAb. We used mice deficient for IL-12p35 or IL-23p19 or IL-12/IL-23p40 to investigate the functional effects of these cytokines in our model situation and identified cellular sources of IL-12 and IL-23 secretion.

Results:

Our results demonstrate that CD40 mediated effector functions in the absence of further T cell help are sufficient to induce a pathogenic systemic and intestinal inflammatory response. Mice stimulated with the anti-CD40 mAb develop epithelial hyperplasia, goblet cell depletion and leucocytic lamina propria infiltrate. This inflammatory response is functionally dependant on TNF-alpha, IFN-gamma as well as IL-12/23p40 secretion. Strikingly CD40-induced colitis but not wasting disease and serum proinflammatory cytokine production depends on IL-23p19 secretion, whereas IL-12p35 secretion controls wasting disease and serum cytokine production but not mucosal immunopathology. IL-23 dependent innate intestinal nflammation is associated with IL-23p19 mRNA producing intestinal dendritic cells.

Summary:

Our experiments identify a novel role for IL-23 as an effector cytokine within the innate intestinal immune system which is involved in a pathogenic immune response.

Conclusion:

The differential role of IL-23 in local but not systemic inflammation suggests it may be of therapeutic potential for intestinal inflammation such as IBD.