Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases

Tien-Yu Huang, Heng-Cheng Chu, Yi-Ling Lin, Chih-Kung Lin, Tsai-Yuan Hsieh, Wei-Kuo Chang, You-Chen Chao, Ching-Len Liao

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases. © 2009 Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)69-82
Number of pages14
JournalToxicology and Applied Pharmacology
Volume237
Issue number1
DOIs
Publication statusPublished - 2009
Externally publishedYes

Fingerprint

Minocycline
Nitric Oxide Synthase Type II
Colitis
Matrix Metalloproteinases
Dextran Sulfate
Trinitrobenzenes
Sulfonic Acids
Tissue
Cytokines
Inflammatory Bowel Diseases
Matrix Metalloproteinase 3
Histology
Mortality
Matrix Metalloproteinase 2
Therapeutics
Weight Loss
Nitric Oxide
Anti-Inflammatory Agents
Body Weight
Messenger RNA

Keywords

  • Colitis
  • Dextran sulfate sodium
  • Inducible nitric oxide synthase
  • Inflammatory bowel diseases
  • Matrix metalloproteinases
  • Minocycline
  • Trinitrobenzene sulfonic acid
  • antibiotic agent
  • collagenase 3
  • dextran sulfate
  • gelatinase A
  • gelatinase B
  • inducible nitric oxide synthase
  • matrix metalloproteinase
  • messenger RNA
  • minocycline
  • nitric oxide
  • stromelysin
  • trinitrobenzenesulfonic acid
  • acute disease
  • animal experiment
  • animal model
  • antiinflammatory activity
  • article
  • chronic disease
  • colitis
  • controlled study
  • disease severity
  • drug dose comparison
  • drug dose increase
  • enteritis
  • experimental model
  • immune response
  • immunohistochemistry
  • intestine cell
  • male
  • mortality
  • mouse
  • nonhuman
  • real time polymerase chain reaction
  • reverse transcription polymerase chain reaction
  • Animals
  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents
  • Cytokines
  • Dextran Sulfate
  • Disease Models, Animal
  • Enzyme Inhibitors
  • Inflammation
  • Male
  • Matrix Metalloproteinases
  • Metronidazole
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase Type II
  • RNA, Messenger
  • Species Specificity
  • Survival Analysis
  • Trinitrobenzenesulfonic Acid
  • Mus

Cite this

Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases. / Huang, Tien-Yu; Chu, Heng-Cheng; Lin, Yi-Ling; Lin, Chih-Kung; Hsieh, Tsai-Yuan; Chang, Wei-Kuo; Chao, You-Chen; Liao, Ching-Len.

In: Toxicology and Applied Pharmacology, Vol. 237, No. 1, 2009, p. 69-82.

Research output: Contribution to journalArticle

Huang, Tien-Yu ; Chu, Heng-Cheng ; Lin, Yi-Ling ; Lin, Chih-Kung ; Hsieh, Tsai-Yuan ; Chang, Wei-Kuo ; Chao, You-Chen ; Liao, Ching-Len. / Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases. In: Toxicology and Applied Pharmacology. 2009 ; Vol. 237, No. 1. pp. 69-82.
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title = "Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases",
abstract = "In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases. {\circledC} 2009 Elsevier Inc. All rights reserved.",
keywords = "Colitis, Dextran sulfate sodium, Inducible nitric oxide synthase, Inflammatory bowel diseases, Matrix metalloproteinases, Minocycline, Trinitrobenzene sulfonic acid, antibiotic agent, collagenase 3, dextran sulfate, gelatinase A, gelatinase B, inducible nitric oxide synthase, matrix metalloproteinase, messenger RNA, minocycline, nitric oxide, stromelysin, trinitrobenzenesulfonic acid, acute disease, animal experiment, animal model, antiinflammatory activity, article, chronic disease, colitis, controlled study, disease severity, drug dose comparison, drug dose increase, enteritis, experimental model, immune response, immunohistochemistry, intestine cell, male, mortality, mouse, nonhuman, real time polymerase chain reaction, reverse transcription polymerase chain reaction, Animals, Anti-Bacterial Agents, Anti-Inflammatory Agents, Cytokines, Dextran Sulfate, Disease Models, Animal, Enzyme Inhibitors, Inflammation, Male, Matrix Metalloproteinases, Metronidazole, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Nitric Oxide Synthase Type II, RNA, Messenger, Species Specificity, Survival Analysis, Trinitrobenzenesulfonic Acid, Mus",
author = "Tien-Yu Huang and Heng-Cheng Chu and Yi-Ling Lin and Chih-Kung Lin and Tsai-Yuan Hsieh and Wei-Kuo Chang and You-Chen Chao and Ching-Len Liao",
note = "被引用次數:29 Export Date: 22 March 2016 CODEN: TXAPA 通訊地址: Chao, Y.-C.; Division of Gastroenterology, Taipei Tzu Chi General Hospital, Taipei, Taiwan 化學物質/CAS: collagenase 3, 175449-82-8; dextran sulfate, 9011-18-1, 9042-14-2; gelatinase A, 146480-35-5; gelatinase B, 146480-36-6; inducible nitric oxide synthase, 501433-35-8; minocycline, 10118-90-8, 11006-27-2, 13614-98-7; nitric oxide, 10102-43-9; stromelysin, 79955-99-0; trinitrobenzenesulfonic acid, 16655-63-3, 2508-19-2; Anti-Bacterial Agents; Anti-Inflammatory Agents; Cytokines; Dextran Sulfate, 9042-14-2; Enzyme Inhibitors; Matrix Metalloproteinases, 3.4.24.-; Metronidazole, 443-48-1; Minocycline, 10118-90-8; Nitric Oxide Synthase Type II, 1.14.13.39; RNA, Messenger; Trinitrobenzenesulfonic Acid, 2508-19-2 製造商: Sigma Aldrich 參考文獻: Amin, A.R., Attur, M.G., Thakker, G.D., Patel, P.D., Vyas, P.R., Patel, R.N., Patel, I.R., Abramson, S.B., A novel mechanism of action of tetracyclines: effects on nitric oxide synthases (1996) Proc. 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year = "2009",
doi = "10.1016/j.taap.2009.02.026",
language = "English",
volume = "237",
pages = "69--82",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases

AU - Huang, Tien-Yu

AU - Chu, Heng-Cheng

AU - Lin, Yi-Ling

AU - Lin, Chih-Kung

AU - Hsieh, Tsai-Yuan

AU - Chang, Wei-Kuo

AU - Chao, You-Chen

AU - Liao, Ching-Len

N1 - 被引用次數:29 Export Date: 22 March 2016 CODEN: TXAPA 通訊地址: Chao, Y.-C.; Division of Gastroenterology, Taipei Tzu Chi General Hospital, Taipei, Taiwan 化學物質/CAS: collagenase 3, 175449-82-8; dextran sulfate, 9011-18-1, 9042-14-2; gelatinase A, 146480-35-5; gelatinase B, 146480-36-6; inducible nitric oxide synthase, 501433-35-8; minocycline, 10118-90-8, 11006-27-2, 13614-98-7; nitric oxide, 10102-43-9; stromelysin, 79955-99-0; trinitrobenzenesulfonic acid, 16655-63-3, 2508-19-2; Anti-Bacterial Agents; Anti-Inflammatory Agents; Cytokines; Dextran Sulfate, 9042-14-2; Enzyme Inhibitors; Matrix Metalloproteinases, 3.4.24.-; Metronidazole, 443-48-1; Minocycline, 10118-90-8; Nitric Oxide Synthase Type II, 1.14.13.39; RNA, Messenger; Trinitrobenzenesulfonic Acid, 2508-19-2 製造商: Sigma Aldrich 參考文獻: Amin, A.R., Attur, M.G., Thakker, G.D., Patel, P.D., Vyas, P.R., Patel, R.N., Patel, I.R., Abramson, S.B., A novel mechanism of action of tetracyclines: effects on nitric oxide synthases (1996) Proc. 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PY - 2009

Y1 - 2009

N2 - In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases. © 2009 Elsevier Inc. All rights reserved.

AB - In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases. © 2009 Elsevier Inc. All rights reserved.

KW - Colitis

KW - Dextran sulfate sodium

KW - Inducible nitric oxide synthase

KW - Inflammatory bowel diseases

KW - Matrix metalloproteinases

KW - Minocycline

KW - Trinitrobenzene sulfonic acid

KW - antibiotic agent

KW - collagenase 3

KW - dextran sulfate

KW - gelatinase A

KW - gelatinase B

KW - inducible nitric oxide synthase

KW - matrix metalloproteinase

KW - messenger RNA

KW - minocycline

KW - nitric oxide

KW - stromelysin

KW - trinitrobenzenesulfonic acid

KW - acute disease

KW - animal experiment

KW - animal model

KW - antiinflammatory activity

KW - article

KW - chronic disease

KW - colitis

KW - controlled study

KW - disease severity

KW - drug dose comparison

KW - drug dose increase

KW - enteritis

KW - experimental model

KW - immune response

KW - immunohistochemistry

KW - intestine cell

KW - male

KW - mortality

KW - mouse

KW - nonhuman

KW - real time polymerase chain reaction

KW - reverse transcription polymerase chain reaction

KW - Animals

KW - Anti-Bacterial Agents

KW - Anti-Inflammatory Agents

KW - Cytokines

KW - Dextran Sulfate

KW - Disease Models, Animal

KW - Enzyme Inhibitors

KW - Inflammation

KW - Male

KW - Matrix Metalloproteinases

KW - Metronidazole

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Nitric Oxide Synthase Type II

KW - RNA, Messenger

KW - Species Specificity

KW - Survival Analysis

KW - Trinitrobenzenesulfonic Acid

KW - Mus

U2 - 10.1016/j.taap.2009.02.026

DO - 10.1016/j.taap.2009.02.026

M3 - Article

VL - 237

SP - 69

EP - 82

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 1

ER -