Differential expression of inflammatory and fibrogenic genes and their regulation by NF-κB inhibition in a mouse model of chronic colitis

Feng Wu, Shukti Chakravarti

Research output: Contribution to journalArticlepeer-review

Abstract

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-κB p65 antisense oligonucleotide reduced but did not abrogate inflammation and fibrosis completely. The antisense oligonucleotide treatment reduced total NF-κB by 60% and downregulated most proinflammatory genes. However, Ccl2, a proinflammatory chemokine known to promote fibrosis, was not downregulated. 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-κB with particular attention to specific proinflammatory and profibrogenic genes that remain active at low levels of NF-κB.

Original languageEnglish (US)
Pages (from-to)6988-7000
Number of pages13
JournalJournal of Immunology
Volume179
Issue number10
StatePublished - Nov 15 2007

ASJC Scopus subject areas

  • Immunology

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