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Osteopontin as two-sided mediator of intestinal inflammation.

Heilmann K, Hoffmann U, Witte E, Loddenkemper C, Sina C, Schreiber S, Hayford C, Holzlöhner P, Wolk K, Tchatchou E, Moos V, Zeitz M, Sabat R, Günthert U, Wittig BM - J. Cell. Mol. Med. (2008)

Bottom Line: This was associated with decreased blood levels of IL-22, a Th17 cytokine that may mediate epithelial regeneration.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.

View Article: PubMed Central - PubMed

Affiliation: Medical Clinic, Charité University Medicine Berlin, Germany.

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.

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OPN deficiency caused different systemic cytokines responses. OPN−/− and WT mice were fed with 2.5% DSS diluted in the drinking water for 7 days, followed by normal drinking water for 10 days and a subsequent second DSS treatment for another 7 days to induce chronic colitis. Mice were analysed before (day 0) or at day 4, day 7 or day 24 after start of DSS treatment. (A) Messenger RNA expression of IL-22, IL-17A, IL-17F, IL-21 and IFN-γ in mesenteric lymph node on day 4 and day 7 was analysed by real-time RT-PCR as relative to HPRT expression. Data from three mice per group are given as the mean ± S.E.M. (B) Blood was collected on day 4 and day 7 for plasma recovery and analysed for the concentrations of IL-22 and TNF-a by ELISA. Data from five mice per group are given as the mean ± S.E.M. (C) Levels of IL-17 were determined in serum of WT and OPN−/− mice with acute DSS colitis. Recombinant OPN were given i.p. PBS served as control. ***P< 0.001. (D) Messenger RNA expression of IL-12p35 in mesenteric lymph node on day 0 and day 24 was analysed by real-time RT-PCR as relative to HPRT expression. Data from three mice per group are given as the mean ± S.E.M.
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fig04: OPN deficiency caused different systemic cytokines responses. OPN−/− and WT mice were fed with 2.5% DSS diluted in the drinking water for 7 days, followed by normal drinking water for 10 days and a subsequent second DSS treatment for another 7 days to induce chronic colitis. Mice were analysed before (day 0) or at day 4, day 7 or day 24 after start of DSS treatment. (A) Messenger RNA expression of IL-22, IL-17A, IL-17F, IL-21 and IFN-γ in mesenteric lymph node on day 4 and day 7 was analysed by real-time RT-PCR as relative to HPRT expression. Data from three mice per group are given as the mean ± S.E.M. (B) Blood was collected on day 4 and day 7 for plasma recovery and analysed for the concentrations of IL-22 and TNF-a by ELISA. Data from five mice per group are given as the mean ± S.E.M. (C) Levels of IL-17 were determined in serum of WT and OPN−/− mice with acute DSS colitis. Recombinant OPN were given i.p. PBS served as control. ***P< 0.001. (D) Messenger RNA expression of IL-12p35 in mesenteric lymph node on day 0 and day 24 was analysed by real-time RT-PCR as relative to HPRT expression. Data from three mice per group are given as the mean ± S.E.M.

Mentions: In the next step we searched for possible systemic differences between WT and OPN−/– mice during acute and chronic DSS-colitis. First, we investigated the cytokine mRNA expression in MLNs. As demonstrated in Fig. 4A, we determined a reduced expression of Th17 cytokines (particularly of IL-22) during acute colitis in MLNs from OPN−/− compared to MLNs from WT mice. In contrast, there were no differences in IFN-γ mRNA expression between WT and OPN−/– in both 4- and 7-day DSS treated mice (Fig. 4A). Correspondingly, the OPN−/– mice showed reduced serum levels of IL-22 (Fig. 4B) at day 4 and IL-17A (Fig. 4C). Interestingly, the levels of TNF-α in these samples were elevated in OPN−/− in comparison to WT mice during acute DSS colitis (Fig. 4B). The application of recombinant OPN increased IL-17 blood levels in OPN−/− mice comparable to those of WT mice (Fig. 4C) (in these samples the levels of IL-22 and TNF-α were not evaluated).


Osteopontin as two-sided mediator of intestinal inflammation.

Heilmann K, Hoffmann U, Witte E, Loddenkemper C, Sina C, Schreiber S, Hayford C, Holzlöhner P, Wolk K, Tchatchou E, Moos V, Zeitz M, Sabat R, Günthert U, Wittig BM - J. Cell. Mol. Med. (2008)

OPN deficiency caused different systemic cytokines responses. OPN−/− and WT mice were fed with 2.5% DSS diluted in the drinking water for 7 days, followed by normal drinking water for 10 days and a subsequent second DSS treatment for another 7 days to induce chronic colitis. Mice were analysed before (day 0) or at day 4, day 7 or day 24 after start of DSS treatment. (A) Messenger RNA expression of IL-22, IL-17A, IL-17F, IL-21 and IFN-γ in mesenteric lymph node on day 4 and day 7 was analysed by real-time RT-PCR as relative to HPRT expression. Data from three mice per group are given as the mean ± S.E.M. (B) Blood was collected on day 4 and day 7 for plasma recovery and analysed for the concentrations of IL-22 and TNF-a by ELISA. Data from five mice per group are given as the mean ± S.E.M. (C) Levels of IL-17 were determined in serum of WT and OPN−/− mice with acute DSS colitis. Recombinant OPN were given i.p. PBS served as control. ***P< 0.001. (D) Messenger RNA expression of IL-12p35 in mesenteric lymph node on day 0 and day 24 was analysed by real-time RT-PCR as relative to HPRT expression. Data from three mice per group are given as the mean ± S.E.M.
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Related In: Results  -  Collection

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fig04: OPN deficiency caused different systemic cytokines responses. OPN−/− and WT mice were fed with 2.5% DSS diluted in the drinking water for 7 days, followed by normal drinking water for 10 days and a subsequent second DSS treatment for another 7 days to induce chronic colitis. Mice were analysed before (day 0) or at day 4, day 7 or day 24 after start of DSS treatment. (A) Messenger RNA expression of IL-22, IL-17A, IL-17F, IL-21 and IFN-γ in mesenteric lymph node on day 4 and day 7 was analysed by real-time RT-PCR as relative to HPRT expression. Data from three mice per group are given as the mean ± S.E.M. (B) Blood was collected on day 4 and day 7 for plasma recovery and analysed for the concentrations of IL-22 and TNF-a by ELISA. Data from five mice per group are given as the mean ± S.E.M. (C) Levels of IL-17 were determined in serum of WT and OPN−/− mice with acute DSS colitis. Recombinant OPN were given i.p. PBS served as control. ***P< 0.001. (D) Messenger RNA expression of IL-12p35 in mesenteric lymph node on day 0 and day 24 was analysed by real-time RT-PCR as relative to HPRT expression. Data from three mice per group are given as the mean ± S.E.M.
Mentions: In the next step we searched for possible systemic differences between WT and OPN−/– mice during acute and chronic DSS-colitis. First, we investigated the cytokine mRNA expression in MLNs. As demonstrated in Fig. 4A, we determined a reduced expression of Th17 cytokines (particularly of IL-22) during acute colitis in MLNs from OPN−/− compared to MLNs from WT mice. In contrast, there were no differences in IFN-γ mRNA expression between WT and OPN−/– in both 4- and 7-day DSS treated mice (Fig. 4A). Correspondingly, the OPN−/– mice showed reduced serum levels of IL-22 (Fig. 4B) at day 4 and IL-17A (Fig. 4C). Interestingly, the levels of TNF-α in these samples were elevated in OPN−/− in comparison to WT mice during acute DSS colitis (Fig. 4B). The application of recombinant OPN increased IL-17 blood levels in OPN−/− mice comparable to those of WT mice (Fig. 4C) (in these samples the levels of IL-22 and TNF-α were not evaluated).

Bottom Line: This was associated with decreased blood levels of IL-22, a Th17 cytokine that may mediate epithelial regeneration.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.

View Article: PubMed Central - PubMed

Affiliation: Medical Clinic, Charité University Medicine Berlin, Germany.

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.

Show MeSH
Related in: MedlinePlus