Corticotropin-releasing factor family peptides (CRF peptides) comprise corticotropin releasing hormone (CRH), urocortin (UCN1), UCN2 and UCN3. CRH is first isolated in the brain and later with UCNs found in many peripheral cells/tissues including the colon. CRH and UCNs function via the two types of receptors, CRF 1 and CRF 2, with CRH mainly acting on CRF 1, UCN1 on both CRF 1&CRF 2 and UCN2-3 on CRF 2. Compiling evidence shows that CRH participates in inflammation and cancers via both indirect central effects related to stress response and direct peripheral influence. CRH, as a stress-response mediator, plays a significant central role in promoting the development of colitis involving colon motility, immunity and gut flora, while a few anti-colitis results of central CRH are also reported. Moreover, CRH is found to directly influence the motility and immune/inflammatory cells in the colon. Likewise, CRH is believed to be greatly related to tumorigenesis of many kinds of cancers including colon cancer via the central action during chronic stress while the peripheral effects on colitis-associated-colon cancer (CAC) are also proved. We and others observe that CRH/CRF 1 plays a significant peripheral role in the development of colitis and CAC in that CRF 1 deficiency dramatically suppresses the colon inflammation and CAC. However, up to date, there still exist not many relevant experimental data on this topic, and there seems to be no absolute clearcut between the central and direct peripheral effects of CRH in colitis and colon cancer. Taken together, CRH, as a critical factor in stress and immunity, may participate in colitis and CAC as a centrally active molecule; meanwhile, CRH has direct peripheral effects regulating the development of colitis and CAC, both of which will be summarized in this review.
Ulcerative colitis (UC) and Crohn’s disease, the common chronic inflammation in the gastrointestinal system, are the two main forms of inflammatory bowel disease (IBD). The precise cause of IBD is not thoroughly known yet. It is observed that UC patients may have a dysregulated mucosal immune response to commensal gut flora, resulting in bowel inflammation characteristically restricted to the mucosal surface in the colon. Chronic inflammation is fundamentally an immune response, which provides microenvironment for tumorigenesis and accounts for a big portion of cancer-causing factors, which is in concert with the case between colitis and colorectal cancer (CRC), although meta-analysis does not show an increased CRC risk over time of inflammation. CRC is one of the most common forms of malignant tumor worldwide, and patients with UC are at higher risk for developing CRC, i.e., colitis-associated colon cancer (CAC), than the general population. Therefore, anti-inflammation treatment is likely a useful approach for preventing the occurrence of CAC. However, despite constant studies and advances in conventional and/or targeted therapy, the survival rate of CRC patients is still not very high.
Corticotropin-releasing factor family peptides (CRF peptides) include 4 members, corticotropin releasing hormone (CRH), urocortin (UCN1), UCN2 and UCN3, mediating their effects via two distinct CRF receptor subtypes, CRF 1 and CRF 2, with CRH being the selective agonist of CRF 1, UCN1 of both, and UCN2-3 of CRF 2.
Corticotropin-releasing family peptides (CRF peptides) and receptors.
Both CRF 1 and CRF 2 belong to the seven transmembrane domain family positively coupled to adenylate cyclase via G proteins. CRH, a 41-amino acid peptide, is observed to activate cAMP/MAPK pathway via CRF 1. It is recognized as a primary regulator of the hypothalamic pituitary axis (HPA axis). The paraventricular nucleus (PVN) of the hypothalamus is the main source for CRH in the brain. CRH, UCNs and the two receptors are also reported to express widely in peripheral cells/tissues, being recognized as important cardiovascular peptides and immune/inflammatory molecules. Their presence in gastrointestinal system has been detected for a long time since decades ago. Moreover, CRH and UCN3 are detected in the human colon and UCN1 mRNA is observed in the rat enteric nervous system. CRF 1 and CRF 2 are encoded by specific genes. CRF 1 is the main type of receptor in the brain while it is also abundant in some peripheral cells/tissues including skin, inflammatory cells and gastrointestinal system. And CRF 2α is predominantly found in neurons and CRF 2β in both brain and peripheral tissues including cardiac & skeletal muscle and the gastrointestinal tract. Both CRF 1 and CRF 2 are distributed within the rat colon: CRF 1 is found in the colonic crypts, the surface epithelium, and the lamina propria of the proximal colonic mucosa. CRF 1 expression is also detected in the myenteric and submucosal nervous plexus. CRF 2 expression is found to be localized mainly in the luminal surface of the crypts and in blood vessels of the submucosal layer. Also in the human colonic mucosa, both CRF 1 and CRF 2 mRNA are detected in lamina propria mononuclear cells. These results support a role for the two receptors’ involvement in regulating peripheral colonic effects of CRH and UCNs. Since this review focuses on the selective CRF 1 agonist, CRH, more about CRH/CRF 1 effects will be discussed.
The hypothalamus-pituitary-adrenal (HPA) axis, functionally a hormone stimulating cascade, mainly CRH-adrenocorticotropin (ACTH)-cortisol axis, is a critical element for stress response and immune/inflammatory processes. Chronic stress, characterized by activation of HPA axis and sympathetic nervous system, has been reported to be an important reason in the development of inflammation and tumorigenesis, suggesting that CRH indirectly participate in inflammation and tumorigenesis via HPA axis as a centrally active molecule. Furthermore, HPA axis communicates with the immune system at multiple levels. Bidirectional interactions between HPA and immunity contribute to their role in inflammation and cancers: HPA activation results in secretion of CRH, ACTH and cortisol modulating the immune response while immunity-related substances, such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor alpha (TNF-α) can backwards stimulate the HPA axis. In addition, relationship between gut microbiome and the brain, i.e. brain-gut-microbiota axis, has attracted much attention for its complicated part in stress and IBD. The imbalance of brain-gut-microbiota axis also leads to dysregulation of the HPA axis. Therefore, it is reasonable that CRH, as the major mediator of stress response, may take a part in IBD and CRC via brain-gut-microbiota axis. Taken together, CRH is suggested to take part in colonic inflammation and inflammation-based tumorigenesis indirectly via HPA axis and brain-gut-microbiota axis.
Moreover, peripherally direct participation of CRH in colonic inflammation has been well proved. The expression of CRH in the large bowel of patients with UC is found considerably enhanced in mucosal inflammatory cells and slightly increased in colonic mucosal epithelial cells, suggesting CRH’s role via modulating intestinal immune/inflammatory system in UC. Also, it is reported that CRH may induce intestinal hyperpermeability in human colon mucosa via mast cells. We and others have also reported the direct peripheral role of CRH/UCNs & receptors in immunity/inflammation and cancers, including colitis and colitis-associated colon cancer (CAC).
In summary, over recent decades, CRF peptides and receptors have been found to be significantly correlated with the bowel inflammation and the development of CAC. However, controversies over the origin of CRH action sites have always been existing. Up-to-date, taken together, it is understandable that CRH, as both a centrally active endocrine hormone and peripherally active peptide, may play an important role in colitis and CAC via both indirect actions regulating chronic stress and direct peripheral effects, although there still lack experimental evidences showing direct relationship between central CRH effect and colitis/CAC and only a few investigations show the direct peripheral effects of CRH on CAC.
Stress, inflammation and colon cancer are highly related, forming a CRH-system driven crosstalk
