rIL-25在急性潰瘍性結腸炎中的抗炎癥效應.pdf

1、Objective: Inflammatory Bowel Diseases (IBD) is a collective term for the unknown etiology gastrointestinal disorders such as Crohn's disease (CD) and Ulcerative Colitis (UC) associated with chronic relapsing inflamm

2、ation. Over recent decades the incidence of IBD has been rising in the world, and IBD will become increasingly common in Asia, as it has been in the last fifty years in Europe and North America. The most recent review of

3、 Chinese literature reveals that 143 511 cases of IBD (140 120 of UC and 3391 of CD) were described during the last 15 years, with an 8.5-fold increase during the last 5 years compared with the first 5 years. Although th

4、e precise etiology of IBD has not been characterized, the most recent hypothesis concerning the under lying disease mechanism states that individuals who have a genetic predisposition, when confronted with unidentified a

5、ggressors from their natural environment, develop a loss of tolerance to luminal bacterial antigens and initiate an uncontrolled inflammatory reaction targeted at the bowel wall and at distant organ systems such as the j

6、oints, skin, or billiard tract. Crohn's disease manifests itself as a chronic granulomatousinflammation of the gastrointestinal tract capable of affecting its entire length with the presence of "skip" lesions. Ulcerative

7、 colitis, on the contrary, presents as a continuous inflammatory lesion air acting the rectum and colon, lacking granulomatouscharacteristics. These two forms of IBD appear to show a distinct profiles of T cell mediated

8、immunity. In patients with Crohn's disease, the patterns of cytokines expressed by mucosal lymphocytes generally tend to be consistent with a T-helper-1(Th1) response, including an early increase in the expression of int

9、erferon (IFN), IL-2, and IL-12, followed by a subsequent increase in tumor necrosis factor-γ (TNF-γ) and IL-18. Furthermore, there also appears to be a compensatory increase inIL-10 and transforming growth factor-ail (TG

10、F-β1) levels. In patients with ulcerative colitis, the pattern of cytokine expression differs from that seen in Crohn's disease, with an increased expression of IL-5, IL-6, IL-10, and IL-13. This Th2 response is up-regul

11、ated in the colon of UC，although the relevance of elevated Th2cytokines to the colonic inflammation has not yet been clarified, an increased pro-inflammatory cytokine production observed seems to be related to the inflam

12、mation. IL-25/IL-17E is a fifth member of the structurally related IL-17 cytokine family.IL-25 was first discovered in human genomic sequence following analysis of human genomic DNA sequence information available in

13、Gen Bank TM (accession number CNSOIDTR). The human IL-25 gene has been mapped to the region 14q11.2 and spans region of about 3595bp (according to Gen Bank accession number NT-026437. Two alternatively spliced mRNA trans

14、cripts of the gene encoding two distinct is forms have been described, the IL-25 is form 1 precursor( Gen Bank accession numberNM-022789 ) and the IL-25 is form 2( Gen Bank accession number NM-172314 ).Both mRNAs c

15、ontain two axons, and is form 2 lack in internal segment compared toisoform 1, leading to a shorter N-terminus. The mRNA is form 1 is predicted to result into a 177-amino acid protein, while the mRNA for is form 2 is pre

16、dicted to encode161-amino acid protein. The two is forms are identical in the last 159 carboxy terminal amino acids. A different in the physiological effect of the two is forms has not yet beendetected.IL-25 is secreted

17、as a disulfide linked homodyne of glycoprotein incorporating cytokine residues, with a molecular weight of 34kDa. Structurally, all six family members (IL-17A to IL-17F) conserved cytokine residues that accounting for c

18、haracteristic of forming a cytokine-knots and in this respect is related to other better-known cytokines such as TGF-β and platelet-derived growth factor. The receptor for IL-25 was first identified as an IL-17B rece

19、ptor (IL-17BR) also called IL-17 receptor homolog 1 (IL-17Rh1) and EVI27. Marine EVI27 was identified through its location at a common site of retroviral integration in BXH2marine myeloid leukemia’s. Co-immunoprecipita

20、tion experiments have shown thatIL-25 is the main legend for 7BR, while IL-17B demonstrated to interact with 17BRwith low affinity. Sequence comparison of the receptors for IL-17A and IL-25 reveals similar overall struct

21、ure with conservation of several cisterns within the extracellulardomains, and also with conserved elements within the intracellular domain, suggesting that these receptors likely engage similar signaling pathways. Indee

22、d, IL-25 was shown to activate NF-κB and to induce the production of chamomile IL-8 in the human renal carcinoma cell line TK-10. IL-17Rh1 shows highest level expression in kidney with moderate expression in multiple oth

23、er organs, whereas IL-25 mRNA was detected at very low levels in several peripheral tissues including colon, uterus, stomach, small intestine, kidney, and lung. Native IL-25 expression has been detected from in vitro

24、-differentiated Th2 cells and in vitro-cultured mast cells. However, when the induction of Th2 cytokines was analyzed in vitro, the major cell type in response to IL-25 appears to be a non-T/non-Bell population expressin

25、g class ⅡMHC and CD11c molecules, a typical accessory cell phenotype. Treatment of mice with purified IL-25 resulted in the production of cytokines IL-4, IL-5, and IL-13, eosinophilia, increased serum Ig, and the develop

26、ment of striking histological changes in the lungs and the gastrointestinal (GI) tract. Similarly, administration of recombinant IL-25 (rIL-25) to mice has been shown to evoke an inflammatory response characterized by th

27、e overproduction of Th2 cytokines, hyper production of immunoglobulin IgA and IgE, overproduction of mucus, epithelial cell hyperplasia, and eosinophilia. DSS-induced experimental colitis is widely regarded as a use

28、ful marine model of IBD, that reliable for the IBD cellular and molecular studies. The DSS model is easily induced, reproducible, and Th1 cytokine response in acute model reported to resemble that observed in human infla

29、mmatory conditions such as IBD. Several animal models for intestinal inflammation have been developed. Oral administration of DSS in drinking water of in several mammals such as mice, rats, guinea pigs and hamsters arabl

30、e to induce not only an acute, but also a chronic colitis after multiple cycles of DSS. Acute colitis in mice is manifested by diarrhea, weight loss, shortening of the colon, mucosal ulceration, and inflammatory cell inf

31、iltration into the left colon. A chronic colitis can be induced in several mammals by feeding them with DSS in their drinking water in cycles of 7 days of DSS followed by 7 days of water. Chronic lesions remarked by incr

32、eased plasma cells, lymphocytes, macrophages, lymphoid aggregates in the lamina propriety as well as the servos and a patchy distribution of inflammation together with fissuring ulcers. The histopathology of this model r

33、esembles to UC and would enable research into the pathogenesis of this disease. Thus, the main objective of this study is to evaluate the effect of rIL-25 on the development of inflammatory Bowel diseases. Conclusion

34、s: 1. DSS-induced ulcerative colitis model is reliable, simple and reproducible model with cytokine profile resemble to human IBD. 2. IL-25 can successful slow down the development of colitis-induced clinical sym

35、ptoms and reduce colonic tissue injury and severity of acute colitis in dose dependent manner. 3. IL-25 can improve mice survival with full restoration of body weight within short space of time. 4. IL-25 expresse

36、d is decrease with increase in colitis. 5. IL-25 induces IL-10, TGF-β1 and IL-23 in the regulation of acute colitis. 6. IL-25 show to play crucial role in the regulation of cotitis by inhibiting or suppressing Th