Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts

Aomatsu, Tomoki; Imaeda, Hirotsugu; Takahashi, Kenichiro; Fujimoto, Takehide; Kasumi, Eiji; Yoden, Atsushi; Tamai, Hiroshi; Fujiyama, Yoshihide; Andoh, Akira

doi:10.3892/ijmm.2012.1094

Cited by 30 publications

(23 citation statements)

References 49 publications

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“…The fact that Ficz-mediated abrogation of p38 and ERK1/2 activation was accompanied by a 60% reduction of cytokine-driven collagen synthesis advocates a major role for MAP kinases in the control of collagen production in CD fibroblasts. This is in line with other reports showing the involvement of MAP kinases in the chemokine and profibrotic factor response of intestinal fibroblasts to inflammatory cytokines [35]. The lack of effect of AhR activation or inhibition on Smad2/3 and NF-κB activation in response to TGF-β or TNF-α is noteworthy as these findings indicate that AhR activation does not induce a state of global unresponsiveness in intestinal fibroblasts, perhaps explaining why proliferation and survival of these cells were not affected by Ficz or CH223191.…”

Section: Discussionsupporting

confidence: 93%

Aryl hydrocarbon receptor‐driven signals inhibit collagen synthesis in the gut

et al. 2016

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Fibrostrictures (FS) are a major complication of Crohn's disease (CD). Pathogenesis of FS is not fully understood, but activation of fibroblasts and excessive collagen deposition are crucial in the development of FS. Here, we investigated the role of aryl hydrocarbon receptor (AhR) in intestinal fibrosis. AhR RNA and protein expression were evaluated in intestinal fibroblasts of CD patients and controls. CD fibroblasts were stimulated with TGF-β1 or TNF-α in the presence or absence of the AhR activator Ficz, an AhR antagonist CH223191, or a specific AhR-silencing RNA. In CD fibroblasts, TGF-β1 and TNF-α increased Col1A1, Col3A1 and α-SMA transcripts and collagen secretion and this effect was reduced by Ficz and upregulated by CH22319. TGF-β1 or TNF-α induced activation of p38 and ERK1/2 MAP kinases was decreased by Ficz and increased by CH223191. The inhibitory effect of Ficz on Map kinase activation and collagen induction was abolished by AhR silencing. To assess the role of AhR in vivo, mice with trinitrobenzene-sulfonic-acid induced colonic fibrosis were given Ficz or CH223191. Mice given either Ficz or CH223191 produced less or more collagen respectively as compared with control mice. Our results indicate that AhR is a negative regulator of profibrotic signals in the gut.

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Section: Discussionsupporting

confidence: 93%

Aryl hydrocarbon receptor‐driven signals inhibit collagen synthesis in the gut

et al. 2016

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“…miR-34a regulates its target gene expression by binding to the 3'-UTR of its target mRNA [34]. Aomatsu et al reported that CXCL10 expression in colonic myofibroblasts is suppressed by tacrolimus and that overexpression of miR-34a represses its target gene CD44 in osteosarcoma cells [35, 36]. The down-regulation of CXCL10 might be caused by c-Fos, a prominent member of the AP-1 family, when mediated by TNF-related apoptosis-inducing ligand [37].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-34a Inhibition of the TLR Signaling Pathway Via CXCL10 Suppresses Breast Cancer Cell Invasion and Migration

Xu¹,

Liu²,

Yang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Breast cancer (BC) starts as a local disease, but it can metastasize to the lymph nodes and distant organs. However, the metastatic process is still poorly understood. The mRNA microarray datasets GSE26910 and GSE33447 show that CXCL10 is up-regulated in BC, and the microRNA microarray dataset GSE38167 and a network meta-analysis of microRNA expression profile studies in human BC suggest that microRNA-34a (miR-34a) is down-regulated in BC. CXCL10 was predicted as a target of miR-34a by microRNA.org. In this study, we uncovered a CXCL10-independent mechanism by which miR-34a exerts its antimetastatic activity in BC. Methods: To investigate the clinical significance of miR-34a in BC, we collected cancer tissues and paracancerous tissues from 258 patients with BC. In addition, a series of inhibitors, mimics, and siRNAs was introduced into MCF-7 and T47D cells to validate the regulatory mechanisms by which miR-34a regulates CXCL10. Next, to better understand the pivotal role of TLR signaling pathway inhibition in MCF-7 and T47D cells, we blocked the TLR signaling pathway using OxPAPC, an antagonist of TLR signaling. Results: Among BC patients, miR-34a was down-regulated, CXCL10 was up-regulated, and the TLR signaling pathway was activated. Determination of luciferase activity revealed that CXCL10 was a target of miR-34a. Through gain- and loss-of-function studies, miR-34a was demonstrated to negatively regulate CXCL10; inhibit activation of the TLR signaling pathway; significantly suppress in vitro cell proliferation, migration, and invasion; and induce apoptosis. Conclusion: Our findings suggest that functional loss or suppression of the tumor suppressor CXCL10 due to induction of miR-34a leads to inhibition of the TLR signaling pathway during breast tumorigenesis, providing a novel target for the molecular treatment of breast malignancies.

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“…Mouse serum was analyzed for the presence of circulating human inflammatory cytokines including: interleukin-6 (IL-6) 16 , interferon γ (IFNγ) 17 , interleukin-5 (IL-5) 18 , monocyte chemotactic protein-1 (MCP-1) 19 , macrophage inflammatory protein (MIP)-1β 20 , interferon inducible protein-10 (IP-10) 21 and tumor necrosis factor α (TNFα) 22 to determine whether the administration of Treg had any impact on the in situ production of these factors. In all cases, levels of circulating inflammatory cytokines were decreased if CB Treg were introduced before administration of PBMC.…”

Section: Resultsmentioning

confidence: 99%

Third-party umbilical cord blood–derived regulatory T cells prevent xenogenic graft-versus-host disease

et al. 2014

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Naturally occurring regulatory T cells (Treg) are emerging as a promising approach for prevention of graft-versus-host Disease (GvHD), which remains an obstacle to the successful outcome of allogeneic hematopoietic stem cell transplantation. However, Treg only constitute 1-5% of total nucleated cells in cord blood (CB) (<3×106 cells) and therefore novel methods of Treg expansion to generate clinically-relevant numbers are needed. Several methodologies are currently being utilized for ex vivo Treg expansion. Here, we report a new approach to expand Treg from CB and demonstrate their efficacy in vitro by blunting allogeneic mixed lymphocyte reactions and in vivo by preventing GvHD using a xenogenic GvHD mouse model. Using magnetic cell sorting, naturally-occurring Treg were isolated from CB by the positive selection of CD25+ cells. These were expanded to clinically-relevant numbers using CD3/28 co-expressing Dynabeads and interleukin (IL)-2. Ex vivo-expanded Treg were CD4+25+FOXP3+127lo and expressed a polyclonal T-cell receptor Vβ repertoire. When compared to conventional T-lymphocytes (CD4+25- cells), Treg consistently showed demethylation of the FOXP3 TSDR promoter region and suppression of allogeneic proliferation responses in vitro. In our NOD-SCID IL-2Rγnull (NSG) xenogeneic model of GvHD, prophylactic injection of 3rd party CB-derived, ex vivo-expanded Treg led to the prevention of GvHD that translated into improved GvHD score, decreased circulating inflammatory cytokines and significantly superior overall survival. This model of xenogenic GvHD can be used to study the mechanism of action of CB Treg as well as other therapeutic interventions.

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Tacrolimus (FK506) suppresses TNF-α-induced CCL2 (MCP-1) and CXCL10 (IP-10) expression via the inhibition of p38 MAP kinase activation in human colonic myofibroblasts

Cited by 30 publications

References 49 publications

Aryl hydrocarbon receptor‐driven signals inhibit collagen synthesis in the gut

Aryl hydrocarbon receptor‐driven signals inhibit collagen synthesis in the gut

MicroRNA-34a Inhibition of the TLR Signaling Pathway Via CXCL10 Suppresses Breast Cancer Cell Invasion and Migration

Third-party umbilical cord blood–derived regulatory T cells prevent xenogenic graft-versus-host disease

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