Corticotrophin-Releasing Factor, Related Peptides, and Receptors in the Normal and Inflamed Gastrointestinal Tract

Abstract

Corticotrophin-releasing factor (CRF) is mainly known for its role in the stress response in the hypothalamic–pituitary–adrenal axis. However, increasing evidence has revealed that CRF receptor signaling has additional peripheral effects. For instance, activation of CRF receptors in the gastrointestinal tract influences intestinal permeability and motility. These receptors, CRF1 and CRF2, do not only bind CRF, but are also activated by urocortins. Most interestingly, CRF-related signaling also assumes an important role in inflammatory bowel diseases in that it influences inflammatory processes, such as cytokine secretion and immune cell activation. These effects are characterized by an often contrasting function of CRF1 and CRF2. We will review the current data on the expression of CRF and related peptides in the different regions of the gastrointestinal tract, both in normal and inflamed conditions. We next discuss the possible functional roles of CRF signaling in inflammation. The available data clearly indicate that CRF signaling significantly influences inflammatory processes although there are important species and inflammation model differences. Although further research is necessary to elucidate this apparently delicately balanced system, it can be concluded that CRF-related peptides and receptors are (certainly) important candidates in the modulation of gastrointestinal inflammation.

The Irritable Bowel Syndrome: How Stress Can Affect the Amygdala Activity and the Brain-Gut Axis

“…Stress is able to disrupt the intestinal epithelial barrier thus increasing the penetration of luminal antigens into the lamina propria, leading to nociceptors sensitization and favoring the development of visceral hypersensitivity (Ait-Belgnaoui, et al 2005). This increase of intestinal permeability is due to an activation of peripheral CRF signaling involving both CRF2 and CRF1 (Buckinx, et al 2011) as well as mast cell activation (Santos, et al 2001). …”

Corticotropin-releasing Factor Receptor 2 Mediates Sex-Specific Cellular Stress Responses

“…The ligand CRF is primarily responsible for regulating and/or initiating stress responses via activation of the HPA axis (1), whereas the urocortins play a vital role in the peripheral stress response. Even though they are ubiquitously present throughout mammalian tissues, CRF, Ucn1-3 and their receptors are variably expressed in the skin (2), skeletal muscle (3), immune system (4), lung (5), heart (6), genitourinary system (7) and gastrointestinal (GI) system (8).…”

P7, a novel antagonist of corticotropin releasing factor receptor type 1 (CRFR1) screened from phage display library

“…Increasing evidence has demonstrated that activation of CRF receptors in the gastrointestinal tract affects intestinal permeability and motility [13]. Specially, CRFR1 promotes intestinal inflammation and endogenous angiogenesis, and antagonist of the receptor exhibits drastic therapeutic effect in animal models [30e32].…”

“…The peptide plays crucial roles in modulating the hypothalamic-pituitary-adrenal (HPA) axis activated by stressful stimuli, as well as behavioral, autonomic, endocrine, reproductive, cardiovascular, gastro-intestinal, metabolic and immune systemic functions, or homeostasis and viability of peripheral organs [2e5]. Moreover, CRF effects have also been found in tumorgenesis [6,7], mood disorders [8], neuroplasticity [9,10], skin stress response system [11], inflammation [12,13], addiction [14e16] and Alzheimer's disease [17]. CRF exerts its biological function via binding to its receptors (CRFR).…”