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

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

Authors:
- Tomoki Aomatsu
- Hirotsugu Imaeda
- Kenichiro Takahashi
- Takehide Fujimoto
- Eiji Kasumi
- Atsushi Yoden
- Hiroshi Tamai
- Yoshihide Fujiyama
- Akira Andoh
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Affiliations: Department of Medicine, Shiga University of Medical Science, Seta Tsukinowa, Otsu 520-2192, Japan, Division of Mucosal Immunology, Graduate School, Shiga University of Medical Science, Seta Tsukinowa, Otsu 520-2192, Japan, Department of Pediatrics, Osaka Medical Collage, Takatsuki 569-8686, Japan
Published online on: August 10, 2012 https://doi.org/10.3892/ijmm.2012.1094
Pages: 1152-1158

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Abstract

In order to investigate the molecular mechanisms underlying the immunosuppressive effects of tacrolimus (FK506) on intestinal inflammation, we examined whether FK506 effects cytokine/chemokine secretion in human colonic myofibroblasts. Human colonic myofibroblasts were isolated from normal human colonic tissue. The mRNA and protein expression for human CCL2 and CXCL10 were analyzed by real-time PCR and ELISA, respectively. p38 MAP kinase activation was evaluated by western blotting. Tacrolimus (1 µM) suppressed tumor necrosis factor (TNF)-α-induced CCL2 and CXCL10 mRNA expression, but did not modulate TNF-α-induced interleukin (IL)-6 or CXCL8 mRNA expression. Dose-dependent, inhibitory effects of tacrolimus on CCL2 and CXCL10 expression were observed at the mRNA and protein levels. Significant inhibitory effects of tacrolimus were observed at concentrations as low as 0.5 µM for CCL2 and 0.1 µM for CXCL10, respectively. TNF-α-induced CCL2 and CXCL10 expression depended on p38 MAP kinase activation, and tacrolimus strongly inhibited the TNF-α-induced phosphorylation of p38 MAP kinase. Tacrolimus did not affect interferon (IFN)-γ-induced signaling transducer and activator of transcription (STAT)-1 phosphorylation, nor did it modulate CXCL10 mRNA and protein expression. In conclusion, tacrolimus suppressed CCL2 and CXCL10 expression in human colonic myofibroblasts. These inhibitory effects of tacrolimus may play key roles in the therapeutic effects of colonic inflammation in inflammatory bowel disease (IBD) patients.

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1.	DK PodolskyInflammatory bowel diseaseN Engl J Med347417429200210.1056/NEJMra020831
2.	A MizoguchiE MizoguchiInflammatory bowel disease, past, present and future: lessons from animal modelsJ Gastroenterol43117200810.1007/s00535-007-2111-318297430
3.	RB SartorMechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitisNat Clin Pract Gastroenterol Hepatol33904072006
4.	A KoboriY YagiH ImaedaInterleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitisJ Gastroenterol459991007201010.1007/s00535-010-0245-120405148
5.	L MayerEvolving paradigms in the pathogenesis of IBDJ Gastroenterol45916201010.1007/s00535-009-0138-3
6.	WA Faubion JrEV Loftus JrWS HarmsenAR ZinsmeisterWJ SandbornThe natural history of corticosteroid therapy for inflammatory bowel disease: a population-based studyGastroenterology121255260200110.1053/gast.2001.2627911487534
7.	KM TaylorPM IrvingOptimization of conventional therapy in patients with IBDNat Rev Gastroenterol Hepatol8646656201110.1038/nrgastro.2011.17221970871
8.	K McSharryAM DalzellK LeiperW El-MatarySystematic review: the role of tacrolimus in the management of Crohn’s diseaseAliment Pharmacol Ther34128212942011
9.	M NaganumaT FujiiM WatanabeThe use of traditional and newer calcineurin inhibitors in inflammatory bowel diseaseJ Gastroenterol46129137201110.1007/s00535-010-0352-z21132334
10.	A BensonT BarrettM SparbergAL BuchmanEfficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn’s disease: a single-center experienceInflamm Bowel Dis147122008
11.	H OgataT MatsuiM NakamuraA randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitisGut5512551262200610.1136/gut.2005.08179416484504
12.	H OgataJ KatoF HiraiDouble-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitisInflamm Bowel Dis18803808201210.1002/ibd.2185321887732
13.	S YamamotoH NakaseM MatsuuraS MasudaK InuiT ChibaTacrolimus therapy as an alternative to thiopurines for maintaining remission in patients with refractory ulcerative colitisJ Clin Gastroenterol45526530201110.1097/MCG.0b013e318209cdc421336140
14.	S YamamotoH NakaseS MikamiLong-term effect of tacrolimus therapy in patients with refractory ulcerative colitisAliment Pharmacol Ther28589597200810.1111/j.1365-2036.2008.03764.x18549460
15.	RW BusuttilJR LakeRole of tacrolimus in the evolution of liver transplantationTransplantation77S44S51200410.1097/01.TP.0000126927.49589.3F15201686
16.	F VincentiA decade of progress in kidney transplantationTransplantation77S52S61200410.1097/01.TP.0000126928.15055.DC15201687
17.	F RusnakP MertzCalcineurin: form and functionPhysiological Rev8014831521200011015619
18.	W LiaoJX LinWJ LeonardIL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiationCurr Opin Immunol23598604201110.1016/j.coi.2011.08.00321889323
19.	V LazarevicLH GlimcherT-bet in diseaseNat Immunol12597606201110.1038/ni.205921685955
20.	UP SinghC VenkataramanR SinghJW Lillard JrCXCR3 axis: role in inflammatory bowel disease and its therapeutic implicationEndocr Metab Immune Disord Drug Targets7111123200710.2174/18715300778083210917584151
21.	SJ ConnorN ParaskevopoulosR NewmanCCR2 expressing CD4⁺ T lymphocytes are preferentially recruited to the ileum in Crohn’s diseaseGut5312871294200415306587
22.	O GripS JanciauskieneAtorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn’s diseasePLoS One4e5263200919421322
23.	C BanksA BatemanR PayneP JohnsonN SheronChemokine expression in IBD. Mucosal chemokine expression is unselectively increased in both ulcerative colitis and Crohn’s diseaseJ Pathol1992835200312474223
24.	HH ZhangK SongRL RabinCCR2 identifies a stable population of human effector memory CD4⁺ T cells equipped for rapid recall responseJ Immunol18566466663201010.4049/jimmunol.090415620980630
25.	IF CharoW PetersChemokine receptor 2 (CCR2) in atherosclerosis, infectious diseases, and regulation of T-cell polarizationMicrocirculation10259264200310.1080/mic.10.3-4.259.26412851643
26.	YG KimN KamadaMH ShawThe Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytesImmunity34769780201110.1016/j.immuni.2011.04.01321565531
27.	M LiuS GuoJM HibbertCXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implicationsCytokine Growth Factor Rev22121130201121802343
28.	S DaneseJF ColombelW ReinischPJ RutgeertsReview article: infliximab for Crohn’s disease treatment - shifting therapeutic strategies after 10 years of clinical experienceAliment Pharmacol Ther338578692011
29.	SB HanauerAA KornbluthJ MessickDT RubinWJ SandbornBE SandsClinical scenarios in IBD: optimizing the use of conventional and biologic agentsInflamm Bowel Dis16S1S11201010.1002/ibd.2152921104734
30.	M AllezS VermeireN MozziconacciThe efficacy and safety of a third anti-TNF monoclonal antibody in Crohn’s disease after failure of two other anti-TNF antibodiesAliment Pharmacol Ther31921012010
31.	YR MahidaJ BeltingerS MakhAdult human colonic subepithelial myofibroblasts express extracellular matrix proteins and cyclooxygenase-1 and −2Am J Physiol273G1341G134819979435560
32.	T OkunoA AndohS BambaInterleukin-1beta and tumor necrosis factor-alpha induce chemokine and matrix metalloproteinase gene expression in human colonic subepithelial myofibroblastsScand J Gastroenterol37317324200210.1080/003655202317284228
33.	A AndohH TakayaT SaotomeCytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblastsGastroenterology119211219200010.1053/gast.2000.853810889171
34.	M ShimadaA AndohK HataIL-6 secretion by human pancreatic periacinar myofibroblasts in response to inflammatory mediatorsJ Immunol168861868200210.4049/jimmunol.168.2.86111777983
35.	O InatomiA AndohK KitamuraH YasuiZ ZhangY FujiyamaButyrate blocks interferon-gamma-inducible protein-10 release in human intestinal subepithelial myofibroblastsJ Gastroenterol40483489200510.1007/s00535-005-1573-4
36.	XF QiDH KimYS YoonEssential involvement of cross-talk between IFN-gamma and TNF-alpha in CXCL10 production in human THP-1 monocytesJ Cell Physiol220690697200910.1002/jcp.2181519472212
37.	C WuY OhmoriS BandyopadhyayG SenT HamiltonInterferon-stimulated response element and NF kappa B sites cooperate to regulate double-stranded RNA-induced transcription of the IP-10 geneJ Interferon Res14357363199410.1089/jir.1994.14.3577897255
38.	DB ShultzMR RaniJD FullerRM RansohoffGR StarkRoles of IKK-beta, IRF1, and p65 in the activation of chemokine genes by interferon-gammaJ Interferon Cytokine Res29817824200910.1089/jir.2009.003419929594
39.	CK WongCB WangWK IpYP TianCW LamRole of p38 MAPK and NF-κB for chemokine release in coculture of human eosinophils and bronchial epithelial cellsClin Exp Immunol139901002005
40.	K HataA AndohM ShimadaIL-17 stimulates inflammatory responses via NF-kappaB and MAP kinase pathways in human colonic myofibroblastsAm J Physiol Gastrointest Liver Physiol282G1035G1044200210.1152/ajpgi.00494.200112016129
41.	HC ReineckerEY LohDJ RinglerA MehtaJL RombeauRP MacDermottMonocyte-chemoattractant protein 1 gene expression in intestinal epithelial cells and inflammatory bowel disease mucosaGastroenterology1084050199510.1016/0016-5085(95)90006-3
42.	M UguccioniP GionchettiDF RobbianiIncreased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitisAm J Pathol155331336199910.1016/S0002-9440(10)65128-010433925
43.	P ManousouG KoliosV ValatasIncreased expression of chemokine receptor CCR3 and its ligands in ulcerative colitis: the role of colonic epithelial cells in in vitro studiesClin Exp Immunol162337347201010.1111/j.1365-2249.2010.04248.x21077277
44.	H HerfarthB Pollok-KoppM GokeA PressM OppermannPolymorphism of CC chemokine receptors CCR2 and CCR5 in Crohn’s diseaseImmunol Lett77113117200111377705
45.	H HerfarthM GokeC HellerbrandPolymorphism of monocyte chemoattractant protein 1 in Crohn’s diseaseInt J Colorectal Dis184014052003
46.	CE EganMD CravenJ LengM MackKW SimpsonEY DenkersCCR2-dependent intraepithelial lymphocytes mediate inflammatory gut pathology during Toxoplasma gondii infectionMucosal Immunol2527535200910.1038/mi.2009.105
47.	UP SinghS SinghDD TaubJW Lillard JrInhibition of IFN-gamma-inducible protein-10 abrogates colitis in IL-10-/-miceJ Immunol17114011406200310.4049/jimmunol.171.3.140112874231
48.	T YoshinoH NakaseY HonzawaImmunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitisInflamm Bowel Dis1620222033201010.1002/ibd.2131820848491