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IL-1 Causes an Increase in Intestinal Epithelial Tight Junction Permeability¹

Rana M. Al-Sadi^* and Thomas Y. Ma^2,*,

^* Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; and Albuquerque Veterans Affairs Medical Center, Albuquerque, NM 87102

IL-1 is a prototypical proinflammatory cytokine that plays a central role in the intestinal inflammation amplification cascade. Recent studies have indicated that a TNF-- and IFN--induced increase in intestinal epithelial paracellular permeability may be an important mechanism contributing to intestinal inflammation. Despite its central role in promoting intestinal inflammation, the role of IL-1 on intestinal epithelial tight junction (TJ) barrier function remains unclear. The major aims of this study were to determine the effect of IL-1 on intestinal epithelial TJ permeability and to elucidate the mechanisms involved in this process, using a well-established in vitro intestinal epithelial model system consisting of filter-grown Caco-2 intestinal epithelial monolayers. IL-1 (0–100 ng/ml) produced a concentration- and time-dependent decrease in Caco-2 transepithelial resistance. Conversely, IL-1 caused a progressive time-dependent increase in transepithelial permeability to paracellular marker inulin. IL-1-induced increase in Caco-2 TJ permeability was accompanied by a rapid activation of NF-B. NF-B inhibitors, pyrrolidine dithiocarbamate and curcumin, prevented the IL-1-induced increase in Caco-2 TJ permeability. To further confirm the role of NF-B in the IL-1-induced increase in Caco-2 TJ permeability, NF-B p65 expression was silenced by small interfering RNA transfection. NF-B p65 depletion completely inhibited the IL-1-induced increase in Caco-2 TJ permeability. IL-1 did not induce apoptosis in the Caco-2 cell. In conclusion, our findings show for the first time that IL-1 at physiologically relevant concentrations causes an increase in intestinal epithelial TJ permeability. The IL-1-induced increase in Caco-2 TJ permeability was mediated in part by the activation of NF-B pathways but not apoptosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Veterans Affairs Merit Review Grant from the Veterans Affairs Research Service and by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO 1-DK-64165-01 (to T.Y.M.).

² Address correspondence and reprint requests to Dr. Thomas Y. Ma, Internal Medicine-Gastroenterology, MSC10 5550, University of New Mexico, Albuquerque, NM 87131-0001. E-mail address: tma{at}salud.unm.edu

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; IL-1ra, IL-1 receptor antagonist; TJ, tight junction; CD, Crohn’s disease; siRNA, small interfering RNA; TER, transepithelial electrical resistance; RT, reverse transcription; MLCK, myosin L chain kinase; PDTC, pyrrolidine dithiocarbamate.

This article has been cited by other articles:

				R. Al-Sadi, D. Ye, K. Dokladny, and T. Y. Ma Mechanism of IL-1{beta}-Induced Increase in Intestinal Epithelial Tight Junction Permeability J. Immunol., April 15, 2008; 180(8): 5653 - 5661. [Abstract] [Full Text] [PDF]