Mesalamine Blocks Tumor Necrosis Factor Growth Inhibition and Nuclear Factor KappaB Activation in Mouse Colonocytes

Overview

Journal Gastroenterology

Specialty Gastroenterology

Date 1999 Feb 25

PMID 10029619

Citations 70

Authors

G C Kaiser

F Yan

D B Polk

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Derivatives of 5-aminosalicylic acid (mesalamine) represent a mainstay in inflammatory bowel disease therapy, yet the precise mechanism of their therapeutic action is unknown. Because tumor necrosis factor (TNF)-alpha is important in the pathogenesis of inflammatory bowel disease, we investigated the effect of mesalamine on TNF-alpha-regulated signal transduction and proliferation in intestinal epithelial cells.

Methods: Young adult mouse colon cells were studied with TNF-alpha, epidermal growth factor, or ceramide in the presence or absence of mesalamine. Proliferation was studied by hemocytometry. Mitogen-activated protein (MAP) kinase activation and IkappaBalpha expression were determined by Western blot analysis. Nuclear transcription factor kappaB (NF-kappaB) nuclear translocation was determined by confocal laser immunofluorescent microscopy.

Results: The antiproliferative effects of TNF-alpha were blocked by mesalamine. TNF-alpha and ceramide activation of MAP kinase were inhibited by mesalamine, whereas epidermal growth factor activation of MAP kinase was unaffected. TNF-alpha-stimulated NF-kappaB activation and nuclear translocation and the degradation of Ikappa-Balpha were blocked by mesalamine.

Conclusions: Mesalamine inhibits TNF-alpha-mediated effects on intestinal epithelial cell proliferation and activation of MAP kinase and NF-kappaB. Therefore, it may function as a therapeutic agent based on its ability to disrupt critical signal transduction events in the intestinal cell necessary for perpetuation of the chronic inflammatory state.

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References

Neurath M, Becker C, Barbulescu K . Role of NF-kappaB in immune and inflammatory responses in the gut. Gut. 1998; 43(6):856-60. PMC: 1727350. DOI: 10.1136/gut.43.6.856. View

Cronstein B, Van de Stouwe M, Druska L, Levin R, Weissmann G . Nonsteroidal antiinflammatory agents inhibit stimulated neutrophil adhesion to endothelium: adenosine dependent and independent mechanisms. Inflammation. 1994; 18(3):323-35. DOI: 10.1007/BF01534273. View

Diaz-Meco M, Dominguez I, Sanz L, Dent P, Lozano J, Municio M . zeta PKC induces phosphorylation and inactivation of I kappa B-alpha in vitro. EMBO J. 1994; 13(12):2842-8. PMC: 395165. DOI: 10.1002/j.1460-2075.1994.tb06578.x. View

Ling L, Cao Z, Goeddel D . NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176. Proc Natl Acad Sci U S A. 1998; 95(7):3792-7. PMC: 19916. DOI: 10.1073/pnas.95.7.3792. View

Zandi E, Chen Y, Karin M . Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate. Science. 1998; 281(5381):1360-3. DOI: 10.1126/science.281.5381.1360. View

Delhase M, Hayakawa M, Chen Y, Karin M . Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science. 1999; 284(5412):309-13. DOI: 10.1126/science.284.5412.309. View

Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M . Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science. 1999; 284(5412):316-20. DOI: 10.1126/science.284.5412.316. View

Zhao Q, Lee F . Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-kappaB through IkappaB kinase-alpha and IkappaB kinase-beta. J Biol Chem. 1999; 274(13):8355-8. DOI: 10.1074/jbc.274.13.8355. View

Thanos D, Maniatis T . NF-kappa B: a lesson in family values. Cell. 1995; 80(4):529-32. DOI: 10.1016/0092-8674(95)90506-5. View

10.

Schreiber S, Nikolaus S, Hampe J . Activation of nuclear factor kappa B inflammatory bowel disease. Gut. 1998; 42(4):477-84. PMC: 1727068. DOI: 10.1136/gut.42.4.477. View

11.

Larrea E, Garcia N, Qian C, Civeira M, Prieto J . Tumor necrosis factor alpha gene expression and the response to interferon in chronic hepatitis C. Hepatology. 1996; 23(2):210-7. PMC: 7165845. DOI: 10.1002/hep.510230203. View

12.

Azad Khan A, Piris J, TRUELOVE S . An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet. 1977; 2(8044):892-5. DOI: 10.1016/s0140-6736(77)90831-5. View

13.

Woronicz J, Gao X, Cao Z, Rothe M, Goeddel D . IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science. 1997; 278(5339):866-9. DOI: 10.1126/science.278.5339.866. View

14.

Whitehead R, VanEeden P, Noble M, Ataliotis P, Jat P . Establishment of conditionally immortalized epithelial cell lines from both colon and small intestine of adult H-2Kb-tsA58 transgenic mice. Proc Natl Acad Sci U S A. 1993; 90(2):587-91. PMC: 45708. DOI: 10.1073/pnas.90.2.587. View

15.

Laemmli U . Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227(5259):680-5. DOI: 10.1038/227680a0. View

16.

Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T . Nuclear factor kappaB is activated in macrophages and epithelial cells of inflamed intestinal mucosa. Gastroenterology. 1998; 115(2):357-69. DOI: 10.1016/s0016-5085(98)70202-1. View

17.

Shanahan F, Niederlehner A, Carramanzana N, Anton P . Sulfasalazine inhibits the binding of TNF alpha to its receptor. Immunopharmacology. 1990; 20(3):217-24. DOI: 10.1016/0162-3109(90)90037-f. View

18.

Barnes P, Karin M . Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997; 336(15):1066-71. DOI: 10.1056/NEJM199704103361506. View

19.

Sartor R . Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am. 1995; 24(3):475-507. View

20.

Yin M, Yamamoto Y, Gaynor R . The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature. 1998; 396(6706):77-80. DOI: 10.1038/23948. View