[The effects of p38 mitogen activated protein kinase inhibitor SB203580 on colonic mucosa tumor necrosis factor alpha expression in ulcerative colitis].
OBJECTIVE
To investigate the expression of phosphorylated p38 mitogen activated protein kinase (MAPK) in colonic mucosa of patients with ulcerative colitis (UC) and the effects of SB203580 which is a p38 MAPK inhibitor on the secretion of TNFalpha in colonic mucosa from patients with UC.


METHODS
Samples of colonic mucosa were collected from 30 UC patients, 20 males and 10 females, aged (33.50 +/- 10.20) years, during enteroscopy. Samples of normal colonic mucosa 10 cm beyond the tumorous tissue were collected from 15 patients with colonic cancer, 10 males and 5 females, aged (46.64 +/- 10.49) years, as normal controls. The samples underwent pathological and immunohistochemical examination. The remaining samples of the colonic mucosa were cultured and divided into 3 groups: UC + SB203580 group (n = 10, SB203580, an inhibitor of p38 MAPK signal pathway, in a concentration of 20 micromol/L was added), UC control group (n = 10, without addition of SB203580), and peri-cancer normal colonic tissue group (n = 10). 5 hours after the culture, immunohistochemistry was used to detect the expression of phosphorylated p38 MAPK and the expression of phosphorylated transcription of activation factor-2 (ATF(2)), which is a downstream molecule of p38 MAPK. ELISA array was used to detect the content of tumor necrosis factor (TNFalpha) in the supernatant.


RESULTS
(1) The A value of phosphorylated p38 MAPK in the colonic mucosa of the UC was 549.22 +/- 32.54, being significantly higher than that of the normal colonic mucosa (143.52 +/- 11.89, P < 0.01). The positive area of the UC group was (1680.61 +/- 115.30) x 10(-5) microm(2), being significantly higher than that of normal colonic mucosa (351.68 +/- 12.73) x 10(-5) microm(2), P < 0.01. (2) The level of TNFalpha in the supernatant of the UC + SB203580 group was (72.07 +/- 20.30) ng/L, being significantly lower than that of the UC control group (549.96 +/- 107.63) ng/L (P < 0.01), but still higher than that of the normal control group (19.44 +/- 3.81) ng/L (P < 0.01). (3) The A value of phosphorylated ATF(2) in the colonic mucosa biopsy specimens of the UC + SB203580 group was 265.82 +/- 40.25, being significantly lower than that of the UC control group (688.32 +/- 47.37, P < 0.01), but still higher than that of the normal control group (120.22 +/- 6.45, P < 0.01). The positive area of phosphorylated ATF(2) in the colonic mucosa biopsy specimens of the UC + SB203580 group was (1213.76 +/- 204.77) x 10(-5) microm(2), being significantly lower than that of the UC control group (2489.02 +/- 193.63) x 10(-5) microm(2), P < 0.01, but no difference in expression of phosphorylated p38 MAPK was found between UC + SB203580 group and UC control group [respectively, A value: 465.64 +/- 38.69 vs 480.34 +/- 38.87, positive area: (1486.26 +/- 165.49) x 10(-5) microm(2) vs (1536.68 +/- 182.16) x 10(-5) microm(2), both P > 0.05].


CONCLUSIONS
p38 MAPK signal transduction pathway plays an important role in the development of UC. Blockade of the signal transduction pathway could ameliorate inflammation, at least in part, by reducing secretion of proinflammatory cytokines, suggesting that p38 MAPK pathway might be a new target for treatment of UC, and SB203580 could be a hopeful novel drug for the treatment of UC.
Yi
Wen-Quan
WQ
Department of Gastroenterology, West China Hospital of Sichuan University, Chengdu 610041, China.
Gan
Hua-Tian
HT
Huang
Xiao-Li
XL
Zhang
Meng
M
Ouyang
Qin
Q
D000293:Adolescent; D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580