ID: 173: IκBζ mediates suppression of secretion of pro-inflammatory cytokines in dendritic cells

Abstract

Maintaining intestinal homeostasis is essential to maintain a balanced immune response in order to fight intestinal intruders but not to overreact towards commensals and nutritional antigens. Dendritic cells (DC) play an important role in balancing the intestinal immune responses as they are among the first antigen presenting cells encountering bacteria at mucosal surfaces. Upon antigen uptake immature DC usually become mature, secrete high amounts of pro-inflammatory cytokines and promote T cell activation. If the intestinal microbiota contains high amounts of commensal Bacteroides vulgatus, DCs become semi-mature and prevent from TH1/TH17-triggered inflammatory responses in animal models, therefore contributing to homeostasis. Compared to mature DCs, smDCs only express very low amounts of pro-inflammatory cytokines like IL-6, IL-12p70, TNFa and IL-1β, that do not affect the activation status of T cells, with the exception of IL-6. Importantly, smDCs encountering a bacterial stimulus that usually induces complete maturation in DCs, do not develop into to mature DCs. This non-responsiveness of smDCs in terms of cytokine secretion is mainly mediated by the host nuclear protein IκBζ. IκBζ expression is caused by TLR induced NFκB transactivation and forms a NFκB feedback inhibition. We suppose that IκBζ expression is also induced by IL-6 binding to the IL-6 receptor via an auto- and paracrine loops. This IL-6 induced IκBζ expression in smDCs, not providing enhanced NFκB transactivation, leads to an inhibition of NFκB activated pro-inflammatory cytokines and therefore promotes the induction of the described non-responsive semi-mature DC phenotypes that helps maintaining the intestinal homeostasis.