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Differential Expression of Inflammatory and Fibrogenic Genes and Their Regulation by NF-B Inhibition in a Mouse Model of Chronic Colitis¹

Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Fibrosis is a major complication of chronic inflammation, as seen in Crohn’s disease and ulcerative colitis, two forms of inflammatory bowel diseases. To elucidate inflammatory signals that regulate fibrosis, we investigated gene expression changes underlying chronic inflammation and fibrosis in trinitrobenzene sulfonic acid-induced murine colitis. Six weekly 2,4,6-trinitrobenzene sulfonic acid enemas were given to establish colitis and temporal gene expression patterns were obtained at 6-, 8-, 10-, and 12-wk time points. The 6-wk point, TNBS-w6, was the active, chronic inflammatory stage of the model marked by macrophage, neutrophil, and CD3⁺ and CD4⁺ T cell infiltrates in the colon, consistent with the idea that this model is T cell immune response driven. Proinflammatory genes Cxcl1, Ccl2, Il1b, Lcn2, Pla2g2a, Saa3, S100a9, Nos2, Reg2, and Reg3g, and profibrogenic extracellular matrix genes Col1a1, Col1a2, Col3a1, and Lum (lumican), encoding a collagen-associated proteoglycan, were up-regulated at the active/chronic inflammatory stages. Rectal administration of the NF-B p65 antisense oligonucleotide reduced but did not abrogate inflammation and fibrosis completely. The antisense oligonucleotide treatment reduced total NF-B by 60% and down-regulated most proinflammatory genes. However, Ccl2, a proinflammatory chemokine known to promote fibrosis, was not down-regulated. Among extracellular matrix gene expressions Lum was suppressed while Col1a1 and Col3a1 were not. Thus, effective treatment of fibrosis in inflammatory bowel disease may require early and complete blockade of NF-B with particular attention to specific proinflammatory and profibrogenic genes that remain active at low levels of NF-B.

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 National Institutes of Health Grant EY11654 and a Senior Research Investigator Award from the Crohn’s and Colitis Foundation of America (to S.C.).

² Address correspondence and reprint requests to Dr. Shukti Chakravarti, Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205. E-mail address: schakra1{at}jhmi.edu

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; ECM, extracellular matrix; qRT-PCR, quantitative RT-PCR; TNBS, 2,4,6,trinitrobenzene sulfonic acid; C_T, cycle threshold.

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