title: Osteopontin as two-sided mediator of intestinal inflammation.
abstract: Osteopontin (OPN) is characterized as a major amplifier of Th1-immune responses. However, its role in intestinal inflammation is currently unknown. We found considerably raised OPN levels in blood of wild-type (WT) mice with dextran sodium sulfate (DSS)-induced colitis. To identify the role of this mediator in intestinal inflammation, we analysed experimental colitis in OPN-deficient (OPN(-/-)) mice. In the acute phase of colitis these mice showed more extensive colonic ulcerations and mucosal destruction than WT mice, which was abrogated by application of soluble OPN. Within the OPN(-/-) mice, infiltrating macrophages were not activated and showed impaired phagocytosis. Reduced mRNA expression of interleukin (IL)-1 beta and matrix metalloproteinases was found in acute colitis of OPN(-/-) mice. This was associated with decreased blood levels of IL-22, a Th17 cytokine that may mediate epithelial regeneration. However, OPN-(/-) mice showed increased serum levels of tumour necrosis factor (TNF)-alpha, which could be due to systemically present lipopolysaccharide translocated to the gut. In contrast to acute colitis, during chronic DSS-colitis, which is driven by a Th1 response of the lamina propria infiltrates, OPN(-/-) mice were protected from mucosal inflammation and demonstrated lower serum levels of IL-12 than WT mice. Furthermore, neutralization of OPN in WT mice abrogated colitis. Lastly, we demonstrate that in patients with active Crohn's disease OPN serum concentration correlated significantly with disease activity. Taken together, we postulate a dual function of OPN in intestinal inflammation: During acute inflammation OPN seems to activate innate immunity, reduces tissue damage and initiates mucosal repair whereas during chronic inflammation it promotes the Th1 response and strengthens inflammation.
authors.affiliation: Medical Clinic, Charité University Medicine Berlin, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Heilmann
authors.forename: Ute
authors.initials: U
authors.lastname: Hoffmann
authors.forename: Ellen
authors.initials: E
authors.lastname: Witte
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Christian
authors.initials: C
authors.lastname: Sina
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Claudia
authors.initials: C
authors.lastname: Hayford
authors.forename: Pamela
authors.initials: P
authors.lastname: Holzlöhner
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wolk
authors.forename: Elianne
authors.initials: E
authors.lastname: Tchatchou
authors.forename: Verena
authors.initials: V
authors.lastname: Moos
authors.forename: Martin
authors.initials: M
authors.lastname: Zeitz
authors.forename: Robert
authors.initials: R
authors.lastname: Sabat
authors.forename: Ursula
authors.initials: U
authors.lastname: Günthert
authors.forename: Bianca Maria
authors.initials: BM
authors.lastname: Wittig
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003424:Crohn Disease / Q000097:blood / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D016207:Cytokines; D053495:Osteopontin; D016264:Dextran Sulfate