Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor κB activation in mouse colonocytes

doi:10.1016/S0016-5085(99)70182-4

Gastroenterology

Volume 116, Issue 3, March 1999, Pages 602-609

https://doi.org/10.1016/S0016-5085(99)70182-4 Get rights and content

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)-α is important in the pathogenesis of inflammatory bowel disease, we investigated the effect of mesalamine on TNF-α–regulated signal transduction and proliferation in intestinal epithelial cells. Methods: Young adult mouse colon cells were studied with TNF-α, epidermal growth factor, or ceramide in the presence or absence of mesalamine. Proliferation was studied by hemocytometry. Mitogen-activated protein (MAP) kinase activation and IκBα expression were determined by Western blot analysis. Nuclear transcription factor κB (NF-κB) nuclear translocation was determined by confocal laser immunofluorescent microscopy. Results: The antiproliferative effects of TNF-α were blocked by mesalamine. TNF-α and ceramide activation of MAP kinase were inhibited by mesalamine, whereas epidermal growth factor activation of MAP kinase was unaffected. TNF-α–stimulated NF-κB activation and nuclear translocation and the degradation of Iκ-Bα were blocked by mesalamine. Conclusions: Mesalamine inhibits TNF-α–mediated effects on intestinal epithelial cell proliferation and activation of MAP kinase and NF-κB. 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.

GASTROENTEROLOGY 1999;116:602-609

Section snippets

Materials

Recombinant murine TNF-α was purchased from Pepro Tech, Inc. (Rocky Hill, NJ). Murine epidermal growth factor (EGF) was the generous gift of Stanley Cohen (Vanderbilt University). C₈-Ceramide was supplied by Biomol Research Laboratories, Inc. (Plymouth Meeting, PA); rabbit antiactive MAP kinase (ERK1/ERK2) polyclonal antibody from Promega (Madison, WI); and murine anti–pan ERK1/ERK2 monoclonal antibody from Transduction Laboratories (Lexington, KY). Recombinant protein A–horseradish peroxidase

Antiproliferative effect of high-dose TNF-α is inhibited by mesalamine

To determine the effect of mesalamine on the antiproliferative response of TNF-α in intestinalepithelial cells, YAMC cells were cultured either with or without mesalamine (20 mmol/L) in serum-starved (0.5% FBS) RPMI 1640 media in the presence or absence of EGF and murine TNF-α for 24 hours at 37°C. Cells were trypsinized and counted by hemocytometry as described previously.⁹ As shown in Figure 1, mesalamine blocks both the direct antiproliferative effect of high-dose TNF-α (100 ng/mL) and the

Discussion

Since their introduction in the 1940s, mesalamine-containing agents have proven effective in both the maintenance and treatment of IBD.³⁰ Mesalamine inhibits cyclooxygenase and lipoxygenase pathways to reduce the production of prostaglandins and leukotrienes, respectively; however, the exact mechanism of action in IBD has eluded investigators.³¹ In this study, we show that mesalamine reverses the antiproliferative effects of TNF-α and profoundly inhibits TNF-α signaling events including the

Acknowledgements

The authors thank Robert Whitehead and the Ludwig Institute (Melbourne, Australia) for generously providing YAMC cells, Lei Sun for his technical skills in performing gel shift assays, and Peter Dempsey and Jonathan Sheehan for advice in immunofluorescent and confocal laser microscopy.

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^☆: Address requests for reprints to: D. Brent Polk, M.D., Division of Gastroenterology and Nutrition, Department of Pediatrics, 21st and Garland Avenue, S-4322 MCN, Nashville, Tennessee 37232-2576. e-mail: [email protected]; fax: (615) 343-8915.

^☆☆: Supported by the National Institutes of Health grants T32 DK07673 and DK02212, and a Crohn's and Colitis Foundation of America research grant.

^★: Immunofluorescent images were collected in part through the use of the Vanderbilt University Medical Center Imaging Core Research Laboratory, supported by National Institutes of Health grants CA68485 and DK20593.

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Alimentary TractMesalamine blocks tumor necrosis factor growth inhibition and nuclear factor κB activation in mouse colonocytes☆,☆☆,★

Abstract

Section snippets

Materials

Antiproliferative effect of high-dose TNF-α is inhibited by mesalamine

Discussion

Acknowledgements

Gastroenterol Clin North Am

J Biol Chem

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

J Biol Chem

Curr Biol

J Biol Chem

Cell

Cell

Immunopharmacology

J Biol Chem

Gastroenterol Clin North Am

Gastroenterology

Gastroenterology

Gastroenterol Clin North Am

Gastroenterology

Gastroenterology

Cell

Cell

Gastroenterology

Tumor necrosis factor receptor-mediated signaling pathways

J Cell Biol

A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease

N Engl J Med

Predominant pathogenic role of tumor necrosis factor alpha in experimental colitis

Eur J Immunol

Nuclear factor κB: a pivotal transcription factor in chronic inflammatory diseases

N Engl J Med

Alimentary Tract
Mesalamine blocks tumor necrosis factor growth inhibition and nuclear factor κB activation in mouse colonocytes☆,☆☆,★