IL-6-Dependent Mucosal Protection Prevents Establishment of a Microbial Niche for Attaching/Effacing Lesion-Forming Enteric Bacterial Pathogens

Abstract

Enteric infections with attaching/effacing lesion-inducing bacterial pathogens are a worldwide health problem. A murine infection model with one such pathogen, Citrobacter rodentium, was used to elucidate the importance of the pleiotropic immune regulator, IL-6, in the pathogenesis of infection. IL-6 was strongly induced in colonic epithelial cells and macrophages upon C. rodentium infection and was required for effective host defense, because mice lacking IL-6 failed to control bacterial numbers 2–3 wk after infection and exhibited increased mortality. IL-6 was not needed for mounting effective T and B cell responses to the pathogens, nor was it important for induction of IFN-γ or TNF-α, cytokines involved in host defense against the bacteria, or the antibacterial effector, NO. Instead, IL-6 played a key role in mucosal protection, since its absence was associated with marked infection-induced apoptosis in the colonic epithelium and subsequent ulcerations. Cell culture studies confirmed that IL-6 protected colon epithelial cells directly against inducible apoptosis, which was accompanied by increased expression of an array of genes encoding antiapoptotic proteins, including Bcl-xL, Mcl-1, cIAP-2, and Bcl-3. Ulcerations appeared to be pathogenetically important, because bacteria localized preferentially to those regions, and chemically induced colonic ulcerations promoted bacterial colonization. Furthermore, blood components likely present in ulcer exudates, particularly alanine, asparagine, and glycine, promoted bacterial growth. Thus, IL-6 is an important regulator of host defense against C. rodentium by protecting the mucosa against ulcerations which can act as a microbial niche for the bacteria.

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

“…It has been previously linked to the production of IL-22 (41), development of Th22 cells (42), and host defense upon C. rodentium infection (21,43). Other cytokines that are also highly expressed at the top of infection, including IL-23, may additionally contribute to STAT3 activation.…”

NOD2 contributes to cutaneous defense againstStaphylococcus aureusthrough α-toxin-dependent innate immune activation

“…In parallel, skin homogenates were prepared and used to determine bacterial numbers by cfu assay, cytokine levels by ELISA, and mRNA expression by real-time PCR. Real-time PCR was performed as previously described (38). Primer sequences are available upon request.…”

“…Primer sequences are available upon request. Myeloperoxidase activity was determined by enzymatic assay as previously described (38).…”

IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling

“…As a consequence, blockade of IL-6 or IL-6 signaling has a profound impact on innate and acquired immune responses. Impaired IL-6 function causes enhanced susceptibility of mice to infection with various pathogens (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) but also results in protection in several mouse models for chronic inflammatory diseases (16)(17)(18). Not surprisingly, IL-6 signaling is also an important target of intervention in chronic inflammatory human diseases such as rheumatoid arthritis and Crohn's disease (19).…”