Corticotropin releasing factor signaling in colon and ileum: regulation by stress and pathophysiological implications.

It is well established that central corticotropin releasing factor (CRF) signaling mediates the gastrointestinal responses to stress. However, as shown in the brain, both CRF receptors and ligands are also widely expressed in the colon and the ileum of humans and rodents, and stress modulates their expression. Several functional studies documented that peripheral injection of CRF or urocortin stimulates colonic transit, motility, Fos expression in myenteric neurons, and defecation through activation of CRF(1) receptors, whereas it decreases ileal contractility via CRF(2) receptors. Additionally, intraperitoneal administration of CRF induces colonic mast cells degranulation via both CRF(1) and CRF(2) receptors and increases ion secretion and mucosal permeability to macromolecules, which can in turn promote intestinal inflammation and alter visceral sensitivity. Most peripheral CRF-induced alterations of colonic and ileal functions mimic effects which are observed after stress exposure, and CRF receptor antagonists given peripherally prevent stress-induced GI dysfunction. Furthermore, CRF peptides can reproduce secretomotor and mucosal alterations in vitro. Therefore, accumulated clinical and preclinical evidence supports in addition to the brain, a role for peripheral CRF signaling in mediating stress-induced effects on gastrointestinal sensorimotor, mucosal and immune functions, that may be components of underlying mechanisms involved in stress-related impact on inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).

Detrimental role for CD4+ T lymphocytes in murine diffuse peritonitis due to inhibition of local bacterial elimination.

BACKGROUND: Abdominal sepsis due to intestinal leakage of endogenous gut bacteria is a life-threatening condition. In healthy individuals, T lymphocytes have essential functions in balancing the immune response to the commensal gut flora. AIM: To determine how T lymphocytes shape the process of diffuse faecal peritonitis. METHODS: In colon ascendens stent peritonitis (CASP), a clinically relevant mouse model of diffuse peritonitis, the kinetics of systemic T cell activation were investigated by assessment of activation markers. CD4(+) T cells were then depleted with monoclonal antibodies, and survival, bacterial dissemination and cytokine concentrations were measured. T cell receptor signalling was blocked with tacrolimus. RESULTS: In diffuse peritonitis, CD4(+) T cells, both Foxp3(-) and Foxp3(+), became systemically involved within hours and upregulated CTLA-4 and other activation markers. Depletion of the CD4(+) T cells enhanced local bacterial clearance from the peritoneal cavity, reduced bacterial dissemination and improved survival. This was accompanied by increased immigration of granulocytes and macrophages into the peritoneum, indicating that CD4(+) T cells inhibit the local innate immune response. Blockade of T cell receptor (TCR) signalling by tacrolimus did not influence the survival in this peritonitis model, showing that the inhibitory effects of the CD4(+) T lymphocytes were independent of TCR-mediated antigen recognition. CONCLUSION: In diffuse peritonitis caused by commensal gut bacteria the CD4(+) T lymphocytes exert a net negative effect on the local anti-bacterial defence, and thereby contribute to bacterial dissemination and poor outcome.

Stress susceptibility predicts the severity of immune depression and the failure to combat bacterial infections in chronically stressed mice.

Chronic psychological stress has been suggested to play a role in disorders in which the immune system unexpectedly fails to respond in a protective manner. Chronic combined acoustic and restraint stress compromises the anti-bacterial defense mechanisms of female BALB/c mice. The immunodeficiency is characterized by an apoptotic loss of lymphocytes, reduced ex vivo-inducibility of TNF but increased inducibility of IL10, reduced T-cell proliferation, and impaired phagocyte functions. Stressed mice develop depression-like behavior that was monitored by a stress severity score (SSS). Besides a strain (BALB/c>CBA) and gender (male>female) dependent susceptibility to chronic stress, inbred mice have an individual coping ability. Importantly, the individual SSS strongly correlates with Escherichia coli dissemination after infection as well as with IL10-inducibility and circulating corticosterone levels of each animal.