Attenuation of IFN-γ-induced B7-H1 expression by 15-deoxy-delta<SUP>12,14</SUP>-prostaglandin J2 via downregulation of the Jak/STAT/IRF-1 signaling pathway

초록

Aim: B7-H1, which belongs to the B7 family of costimulatory molecules, is implicated in the ability of tumors to evade the host immune response. The development of evasion mechanisms within the tumor microenvironment may be responsible for poor therapeutic responses. In this manuscript, we report that the 15-deoxy-delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), peroxisome proliferator-activated receptor gamma (PPAR gamma) activator leads to the downregulation of the cancer-associated expression of B7-H1 in response to interferon-gamma (IFN-gamma) and the associated signaling cascades. Main methods: The expression of B7-H1 from IFN-gamma-induced B16F10 melanoma cells was measured with flow cytometric analysis. The regulatory mechanisms of 15d-PGJ(2) on cellular signaling pathways were examined using Western blot and electrophoretic mobility shift assays. Key findings: The flow cytometric analysis revealed that the B7-H1 costimulatory molecule is significantly upregulated in B16F10 melanoma cells by stimulation with IFN-gamma. However, 15d-PGJ(2) strongly downregulates B7-H1 expression in IFN-gamma-stimulated B16F10 melanoma cells. Furthermore, the significant damping effect of 15d-PGJ(2) on B7-H1 expression involves the inhibition of the tyrosine phosphorylation of Janus kinase (Jak) and signal transducer(s) and activator(s) of transcription (STAT) and, thereby, the interferon regulatory factor-1 (IRF-1) trans-activation of STAT. These effects of 15d-PGJ(2) were not abrogated by the PPAR gamma antagonist GW9662, indicating that they occur through a PPAR gamma-independent mechanism. Significance: In this study, we demonstrate that 15d-PGJ(2) suppresses the IFN-gamma-elicited expression of B7-H1 by the inhibition of IRF-1 transcription via the Jak/STAT signaling pathway through a PPAR gamma-independent mechanism in mouse melanoma cells. (C) 2014 Elsevier Inc. All rights reserved.

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