Sulindac, a nonsteroidal anti-inflammatory drug, selectively inhibits interferon-γ-induced expression of the chemokine CXCL9 gene in mouse macrophages

Sakaeda, Yoshiichi; Hiroi, Miki; Shimojima, Takahiro; Iguchi, Mayumi; Kanegae, Haruhide; Ohmori, Yoshihiro

doi:10.1016/j.bbrc.2006.09.058

Cited by 10 publications

(11 citation statements)

References 26 publications

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“…The mechanisms underlying the inhibitory effect of high concentrations on CXCR3 ligand release remain unclear, but a possible explanation is that the COX inhibitory effects of celecoxib at high concentrations are superimposed by its COX-independent effects, particularly the inactivation of NF-κB signalling [49]. Similiar findings have been reported for the NSAID sulindac, that, in contrast to ASA, impaired CXCL9 mRNA synthesis in mouse macrophages [50]. Moreover, in a murine model of colorectal cancer, celecoxib showed COX-independent anti-tumor activity and even decreased the number of infiltrating lymphocytes [51], consistent with an impairment of CXCR3 ligand release.…”

Section: Discussionmentioning

confidence: 99%

Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer

et al. 2012

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IntroductionIn murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes. In human breast cancer, CXCL9 mRNA overexpression correlates with the number of tumor infiltrating lymphocytes and predicts response to different chemotherapeutic regimens. Raising the intratumoral CXCR3 ligand concentration is therefore a possible way to enhance immune intervention in breast cancer. Little is known, however, about expression levels and regulation of these chemokines in human breast cancer. Since the inhibition of cyclooxygenases (COX) has been shown to reduce tumor growth and incidence of metastases in a lymphocytic and IFN-γ dependent manner, we argued that COX isoenzymes are a pharmacologic target to increase intratumoral CXCR3 ligand concentration in human breast cancer.MethodsCXCL9 was visualized in breast cancer specimens by immunohistochemistry, expression levels of CXCL9 and cyclooxygenases were determined by ELISA and western blotting, respectively. For regulation studies, Michigan Cancer Foundation-7 (MCF-7) and M.D. Anderson - Metastatic Breast 231 (MDA-MB 231) breast cancer cells were stimulated with IFN-γ with or without prostaglandin E2 (PGE2) or COX inhibitors (indomethacin, acetylsalicylic acid (ASA), celecoxib). CXCR3 ligand release from cells was measured by ELISA.ResultsWithin the tumor microenvironment, cancer cells are the major source of CXCL9. PGE2 impairs IFN-γ mediated CXCL9 and CXCL10 release from MCF-7 and MDA-MB 231 cells, and inhibition of endogenous cyclooxygenases by indomethacin or ASA correspondingly increases this secretion. Otherwise, high concentrations of the Cyclooxygenase-2 (COX-2) specific antagonist celecoxib have opposite effects and impair CXCL9 and CXCL10 release. In human breast cancer tissue specimens there is an inverse correlation between COX-2 overexpression and CXCL9 concentration, suggesting that the observed in vitro effects are of importance in vivo as well.ConclusionsSuppressing endogenous PGE2 synthesis by cyclooxygenase inhibition increases CXCL9 and CXCL10 release from breast cancer cells and is therefore a pharmacologic candidate to enhance intratumoral immune infiltration. Yet, to this end the unselective COX inhibitors ASA and indomethacin seem preferable to celecoxib that at higher concentrations reduces CXCR3 ligand release most probably due to COX independent mechanisms.

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Section: Discussionmentioning

confidence: 99%

Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer

et al. 2012

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“…In this study we focused on the influence of PTS2 on the expression of IP-10/CXCL10, an IFN-c inducible chemokine whose transcriptional regulation is mainly dependent on JAK/STAT1 signaling pathway activation. Sakaeda et al [41] showed that IFN-c-stimulated IP-10/CXCL10 expression in RAW264.7 cells. In the current study, we demonstrated that IFN-c-induced up-regulation of IP-10/ CXCL10 in RAW264.7 cells was dose and Fig.…”

Section: Discussionmentioning

confidence: 99%

Dipyrithione inhibits IFN-γ-induced JAK/STAT1 signaling pathway activation and IP-10/CXCL10 expression in RAW264.7 cells

Han

Liu

et al. 2010

Inflamm. Res.

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“…Identification of the pathological pathways involved in macrophage dysfunction in endometriosis may lead to better targeted therapies in the future, while research into molecules inhibiting oxidative stress and NF-kB pathways in activated macrophages (35) could well prove to be a major field of investigation in the development of medical therapy for endometriosis.…”

Section: Lousse Iron and Macrophages In Endometriosis Fertil Sterilmentioning

confidence: 99%

Iron storage is significantly increased in peritoneal macrophages of endometriosis patients and correlates with iron overload in peritoneal fluid

Lousse

Defrère

Langendonckt

et al. 2009

Fertility and Sterility

103

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Sulindac, a nonsteroidal anti-inflammatory drug, selectively inhibits interferon-γ-induced expression of the chemokine CXCL9 gene in mouse macrophages

Cited by 10 publications

References 26 publications

Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer

Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer

Dipyrithione inhibits IFN-γ-induced JAK/STAT1 signaling pathway activation and IP-10/CXCL10 expression in RAW264.7 cells

Iron storage is significantly increased in peritoneal macrophages of endometriosis patients and correlates with iron overload in peritoneal fluid

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