Unique gene expression profiles of heart allograft rejection in the interferon regulatory factor-1-deficient mouse

Erickson, Laurie; Crews, Gladys; Fan, Ping; Fisniku, Ogert; Jang, Mei Shiang; Wynn, Carmen; Kobayashi, Masakazu; Jiang, Hongsi

doi:10.1016/j.trim.2004.06.003

Cited by 10 publications

(5 citation statements)

References 28 publications

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“…Using an Helicobacter pylori infection model, Kudo et al (47) showed that maximal H. pylori-induced CCL5 gene transcription required the presence of the interferon-stimulated response element (ISRE) and the cyclic AMP-responsive element. Our previous studies further mapped the IFN␥-inducible ISRE in the CCL5 promoter as IRF1-RE (40,48).…”

Section: Discussionmentioning

confidence: 99%

Tumor-secreted PGE2 Inhibits CCL5 Production in Activated Macrophages through cAMP/PKA Signaling Pathway

Zhang

Liu

2011

Journal of Biological Chemistry

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One of the major characteristics of tumors is their ability to evade immunosurveillance through altering the properties and functions of host stromal and/or immune cells. CCL5 has been shown to play important roles in T cell proliferation, IFN-␥, and IL-2 production, which promotes the differentiation and proliferation of Th1 cells important for immune defense against intracellular infection. In this study we found that tumor-bearing mice were more susceptible to bacterial infection and showed reduced CCL5 levels in serum during endotoxic shock. Our data further demonstrated that the soluble factors secreted by mammary gland tumor cells but not normal mammary gland epithelial cells inhibited CCL5 expression in macrophages in response to LPS, but not to TNF-␣ stimulation. The inhibitory effect of tumor-secreted molecules on LPS-induced CCL5 expression was regulated at the post-transcriptional level. Blocking PGE 2 synthesis by NS398 or through the use of PGE 2 receptor antagonists AH-6809 (EP2 antagonist) and AH-23848 (EP4 antagonist) completely reversed the inhibitory effect of tumor-conditioned medium (TCM) on LPS-induced CCL5 expression. Moreover, PGE 2 and the cAMP analog forskolin could mimic tumor-mediated CCL5 inhibition, and the inhibitory effects of TCM, PGE 2 , and cAMP analog on LPS-induced CCL5 expression could be completely reversed by the PKA inhibitor H89. Furthermore, blocking PGE 2 synthesis in vivo led to partial recovery of CCL5 production during endotoxic shock. Taken together, our data indicate that PGE 2 secreted from breast cancer cells suppresses CCL5 secretion in LPS-activated macrophages through a cAMP/PKA signaling pathway, which may result in suppression of host immune responses against subsequent bacterial infection.

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Section: Discussionmentioning

confidence: 99%

Tumor-secreted PGE2 Inhibits CCL5 Production in Activated Macrophages through cAMP/PKA Signaling Pathway

Zhang

Liu

2011

Journal of Biological Chemistry

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“…In addition, IRF-1 -/- mice have defects not observed in IFN-γ or IFN-γ- receptor -/- animals, (such as alterations in CD8+ T cells and thymocyte development), supporting the existence of an IFN-γ-independent activation pathway of IRF-1, [ 54 , 185 ]. Vice versa , even supposing a central role for this protein in the induction of pro-inflammatory mediators, a recent microarray study in heart transplanted mice suggested that IRF-1 functions could be bypassed by other mediators [ 186 ]. That same study showed that the expression profile of the allograft from IRF-1 -/- mice and wild type mice were nearly identical to each other and very different from the profile of isograft control.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis

et al. 2011

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In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.).Here, we challenge the ICR hypothesis by using a meta-analytical approach and systematically reviewing microarray studies evaluating gene expression on tissue biopsies during acute allograft rejection. We found the pillars of the ICR consistently present among the studies reviewed, despite implicit heterogeneity.Additionally, we provide a descriptive mechanistic overview of acute allograft rejection by describing those molecular pathways most frequently encountered and thereby thought to be most significant. The biological role of the following molecular pathways is described: IFN-γ, CXCR3/CCR5 ligand, IEF genes, TNF-α, IL-10, IRF-1/STAT-1, and complement pathways. The role of NK cell, B cell and T-regulatory cell signatures are also addressed.

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“…It has been reported that transcription factors such as interferon regulatory factor-3, STAT1 and NF-κB mediate CCL5 transcription and production [16], [17]. Using an Helicobacter pylori infection model, Kudo et al showed that maximal H. pylori -induced CCL5 gene transcription required the presence of the interferon-stimulated response element (ISRE) and the cyclic AMP-responsive element [18]. Our previous studies further mapped the IFN-γ-inducible ISRE in the CCL5 promoter as IRF1-RE [19], [20].…”

Section: Introductionmentioning

confidence: 99%

Regulation of CCL5 Expression in Smooth Muscle Cells Following Arterial Injury

et al. 2012

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Chemokines play a crucial role in inflammation and in the pathophysiology of atherosclerosis by recruiting inflammatory immune cells to the endothelium. Chemokine CCL5 has been shown to be involved in atherosclerosis progression. However, little is known about how CCL5 is regulated in vascular smooth muscle cells. In this study we report that CCL5 mRNA expression was induced and peaked in aorta at day 7 and then declined after balloon artery injury, whereas IP-10 and MCP-1 mRNA expression were induced and peaked at day 3 and then rapidly declined.The expression of CCL5 receptors (CCR1, 3 & 5) were also rapidly induced and then declined except CCR5 which expression was still relatively high at day 14 after balloon injury. In rat smooth muscle cells (SMCs), similar as in aorta CCL5 mRNA expression was induced and kept increasing after LPS plus IFN-gamma stimulation, whereas IP-10 mRNA expression was rapidly induced and then declined. Our data further indicate that induction of CCL5 expression in SMCs was mediated by IRF-1 via binding to the IRF-1 response element in CCL5 promoter. Moreover, p38 MAPK was involved in suppression of CCL5 and IP-10 expression in SMCs through common upstream molecule MKK3. The downstream molecule MK2 was required for p38-mediated CCL5 but not IP-10 inhibition. Our findings indicate that CCL5 induction in aorta and SMCs is mediated by IRF-1 while activation of p38 MAPK signaling inhibits CCL5 and IP-10 expression. Methods targeting MK2 expression could be used to selectively regulate CCL5 but not IP-10 expression in SMCs.

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Unique gene expression profiles of heart allograft rejection in the interferon regulatory factor-1-deficient mouse

Cited by 10 publications

References 28 publications

Tumor-secreted PGE2 Inhibits CCL5 Production in Activated Macrophages through cAMP/PKA Signaling Pathway

Tumor-secreted PGE2 Inhibits CCL5 Production in Activated Macrophages through cAMP/PKA Signaling Pathway

Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis

Regulation of CCL5 Expression in Smooth Muscle Cells Following Arterial Injury

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