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Infection and Immunity, January 2007, p. 471-480, Vol. 75, No. 1
0019-9567/07/$08.00+0     doi:10.1128/IAI.02039-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Trefoil Family Factor 2 Is Expressed in Murine Gastric and Immune Cells and Controls both Gastrointestinal Inflammation and Systemic Immune Responses{triangledown}

Evelyn A. Kurt-Jones,1* LuCheng Cao,1 Frantisek Sandor,1,2 Arlin B. Rogers,3 Mark T. Whary,3 Prashant R. Nambiar,3 Anna Cerny,1 Glennice Bowen,1 Jing Yan,1 Shigeo Takaishi,4 Alfred L. Chi,4 George Reed,1 JeanMarie Houghton,1,4 James G. Fox,3 and Timothy C. Wang1,4*

Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building, Worcester, Massachusetts 01605,1 Department of Immunology, Comenius University School of Medicine, University Hospital Bratislava, Department of Oncology, Clinic of Pneumology, Bratislava, Slovak Republic,2 Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,3 Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building, Worcester, Massachusetts 016054

Received 19 December 2005/ Returned for modification 8 February 2006/ Accepted 26 October 2006

Trefoil family factor 2 (TFF2), also known as spasmolytic peptide, is a low-molecular-weight protein that is upregulated in gastric tissues infected with Helicobacter or having other inflammatory conditions, but a precise function is yet to be elucidated. The role of TFF2 in the development of gastritis, colitis, and inflammatory cytokine responses was examined both in vivo and in vitro using wild-type and TFF2 knockout mice. TFF2 knockout and wild-type mice were infected with Helicobacter felis (H. felis) to induce gastritis. Colitis was induced in TFF2 knockout and wild-type mice by administering dextran sodium sulfate (DSS) in drinking water. Histopathology, clinical disease (colitis), and antibody levels (H. felis) were examined. TFF2 expression in tissues was determined by reverse transcriptase PCR, and the inflammatory and proliferative responses of TFF2-expressing macrophages and spleen cells were examined by cytokine enzyme-linked immunosorbent assay, thymidine incorporation, and gene array studies. TFF2 knockout mice have increased susceptibility to H. felis-induced gastritis, with enhanced gastric inflammation. They were also more susceptible to DSS-induced colitis, with prolonged colonic hemorrhage and persistent weight loss. Remarkably, TFF2 expression was not limited to the gastrointestinal tract, as suggested in previous studies, but was also present in macrophages and lymphocytes. The inflammatory and proliferative responses of these immune cell types were dysregulated in TFF2 knockout mice. TFF2–/– cells were hyperresponsive to interleukin 1 beta stimulation but showed normal responses to lipopolysaccharide, suggesting a specific role for TFF2 in interleukin 1 receptor but not Toll-like receptor 4 signaling via their Toll-interleukin 1 resistance domains. TFF2–/– lymphocytes also produced higher levels of interleukin 2 than wild-type cells. Thus, TFF2 was expressed in the gastrointestinal cells and in immune cells and was a negative regulator of gastrointestinal inflammation and immune cell cytokine responses. Our studies suggest that TFF2 not only controls gastrointestinal repair but also regulates mononuclear cell inflammatory responses.

* Corresponding author. Mailing address for E.K.-J.: University of Massachusetts Medical School, Department of Medicine, 364 Plantation Street, Lazare Research Building Rm. 226, Worcester, MA 01605. Phone: (508) 856-3531. Fax: (508) 856-6176. E-mail: evelyn.kurt-jones{at}umassmed.edu. Present address for T.C.W.: Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, Box 83, New York, NY 10032. Phone: (212) 342-3412. Fax: (212) 305-6443. E-mail: tcw21{at}columbia.edu.

{triangledown} Published ahead of print on 13 November 2006.

Editor: J. L. Flynn

Infection and Immunity, January 2007, p. 471-480, Vol. 75, No. 1
0019-9567/07/$08.00+0     doi:10.1128/IAI.02039-05
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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