Background and Aims: The coordinated expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) plays a crucial role in tissue remodeling. We investigated the effects of fibroblast growth factor (FGF)-2 on the secretion of MMPs and TIMPs in human intestinal subepithelial myofibroblasts (SEMFs). Methods: The secretion of MMP-s and TIMPs was determined by ELISA or Western blotting. The mRNA expression of MMPs and TIMPs was assessed by Northern blotting. The activating protein (AP)-1-DNA binding activity was evaluated by electrophoretic gel mobility shift assays (EMSA). Results: Unstimulated intestinal SEMFs constitutively secreted MMP-2 and TIMP-2. FGF-2 stimulated MMP-1, MMP-3 and TIMP-1 secretion, but did not affect MMP-2 or TIMP-2 secretion. FGF-2 induced AP-1-DNA binding activity, and the c-Jun/AP-1 inhibitor curcumin attenuated the FGF-2-induced MMP-1, -3 and TIMP-1 mRNA expression. Mitogen-activated protein (MAP) kinase inhibitors (U0126 and PD098059) also blocked the MMP-1, -3 and TIMP-1 secretion. Furthermore, FGF-2 dose-dependently induced FGF-2 mRNA expression in these cells. Conclusions: FGF-2 may be one of important regulatory factors for extracellular matrix turnover via a modulation of MMP and TIMP secretion from SEMFs.

1.
Nagase H, Woessner JFJ: Matrix metalloproteinases. J Biol Chem 1999;274:21491–21494.
[PubMed]
2.
Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM: Matrix metalloproteinases: Biologic activity and clinical implications. J Clin Oncol 2000;18:1135–1149.
[PubMed]
3.
Vicenti MP: The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes: Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol 2001;151:121–148.
4.
MacDonald TT, Bajaj-Elliott M, Pender SLF: T cells orchestrate intestinal mucosal shape and integrity. Immunol Today 1999;20:505–510.
[PubMed]
5.
Pallone F, Monteleone G: Mechanisms of tissue damage in inflammatory bowel disease. Curr Opin Gastroenterol 2001;17:307–312.
6.
Stallmach A, Chan CC, Ecker KW, Feifel G, Herbst H, Schuppan D, Zeitz M: Comparable expression of matrix metalloproteinases 1 and 2 in pouchitis and ulcerative colitis. Gut 2000;47:415–422.
[PubMed]
7.
von Lampe B, Barthel B, Coupland SE, Riecken EO, Rosewicz S: Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut 2000;47:63–73.
[PubMed]
8.
Louis E, Ribbens C, Godon A, Franchimont D, De Groote D, Hardy N, Boniver J, Belaiche J, Malaise M: Increased production of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinase-1 by inflamed mucosa in inflammatory bowel disease. Clin Exp Immunol 2000;120:241–246.
[PubMed]
9.
Arihiro S, Ohtani H, Hiwatashi N, Torii A, Sorsa T, Nagura H: Vascular smooth muscle cells and pericytes express MMP-1, MMP-9, TIMP-1 and type I procollagen in inflammatory bowel disease. Histopathology 2001;39:50–59.
10.
Jobson TM, Billington CK, Hall IP: Regulation of proliferation of human colonic subepithelial myofibroblasts by mediators important in intestinal inflammation. J Clin Invest 1998;101:2650–2657.
[PubMed]
11.
Hata K, Andoh A, Shimada M, Fujino S, Bamba S, Araki Y, Okuno T, Fujiyama Y, Bamba T: IL-17 stimulates inflammatory responses via NF-κB and MAP kinase pathways in human colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol 2002;282:G1035–1044.
12.
Pender SL, Breese EJ, Gunther U, Howie D, Wathen NC, Schuppan D, MacDonald TT: Suppression of T cell-mediated injury in human gut by interleukin 10: Role of matrix metalloproteinases. Gastroenterology 1998;115:573–583.
[PubMed]
13.
Daum S, Bauer U, Foss HD, Schuppan D, Stein H, Riecken EO, Ullrich R: Increased expression of mRNA for matrix metalloproteinases-1 and -3 and tissue inhibitor of metalloproteinases-1 in intestinal biopsy specimens from patients with coeliac disease. Gut 1999;44:17–25.
[PubMed]
14.
Okuno T, Andoh A, Bamba S, Araki Y, Fujiyama Y, Fujimiya, Bamba T:. Interleukin-1β and tumor necrosis factor-α induce chemokine and matrix metalloproteinase gene expression in human colonic subepithelial myofibroblasts. Scand J Gastroenterol 2002;37:317–324.
15.
Bamba S, Andoh A, Yasui H, Araki Y, Bamba T, Fujiyama Y: Matrix metalloproteinase-3 secretion from human colonic subepithelial myofibroblasts: Role of interleukin-17. J Gastroenterol 2003;38:548–554.
16.
MacNaul KL, Chartrain N, Lark M, Tocci MJ, Hutchinson NI: Discoordinate expression of stromelysin, collagenase, and tissue inhibitor of metalloproteinases-1 in rheumatoid human synovial fibroblasts: Synergistic effects of interleukin-1 and tumor necrosis factor-alpha on stromelysin expression. J Biol Chem 1990;265:17238–17245.
17.
Rawdanowicz TJ, Hampton AL, Nagase H, Woolley DE, Salamonsen LA: Matrix metalloproteinase production by cultured human endometrial stromal cells: Identification of interstitial collagenase, gelatinase-A, gelatinase-B, and stromelysin-1 and their differential regulation by interleukin-1 alpha and tumor necrosis factor-alpha. J Clin Endocrinol Metab 1994;79:530–536.
[PubMed]
18.
Jasser MZ, Mitchell PG, Cheung HS: Induction of stromelysin-1 and collagenase synthesis in fibrochondrocytes by tumor necrosis factor-alpha. Matrix Biol 1994;14:241–249.
[PubMed]
19.
Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB: Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol 1999;277:C183–201.
20.
Mahida YR, Beltinger J, Makh S, Goke M, Gray T, Podolsky DK, Hawkey CJ: Adult human colonic subepithelial myofibroblasts express extracellular matrix proteins and cyclooxygenase-1 and -2. Am J Physiol 1997;273:G1341–1348.
21.
Fujimoto N, Mouri N, Iwata K, Ohuchi E, Okada Y, Hayakawa T. A one-step sandwich enzyme immunoassay for human matrix metalloproteinase 2 (72-kD gelatinase/type IV collagenase) using monoclonal antibodies. Clin Chim Acta 1993;221:91–103.
[PubMed]
22.
Kodama S, Iwata K, Iwata H, Yamashita K, Hayakawa T: Rapid one-step sandwich enzyme immunoassay for tissue inhibitor of metalloproteinases: An application for rheumatoid arthritis serum and plasma. J Immunol Methods 1990;127:103–108.
[PubMed]
23.
Merlos-Suarez A, Ruiz-Paz S, Baselga J, Arribas J: Metalloprotease-dependent protransforming growth factor-alpha ectodomain shedding in the absence of tumor necrosis factor-alpha-converting enzyme. J Biol Chem 2001;276:48510–48517.
[PubMed]
24.
Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156–159.
[PubMed]
25.
Andoh A, Takya H, Saotome T, Shimada M, Hata T, Araki Y, Nakamura F, Shintani Y, Fujiyama Y, Bamba T: Cytokine regulation of chemokine (IL-8, MCP-1, and RANTES) gene expression in human pancreatic periacinar myofibroblasts. Gastroenterology 2000;119:211–219.
[PubMed]
26.
Goldberg GI, Wilhelm SM, Kronberger A, Bauer EA, Grant GA, Eisen AZ: Human fibroblast collagenase: Complete primary structure and homology to an oncogene transformation-induced rat protein. J Boil Chem 1986;261:6600–6605.
27.
Collier IE, Wilhelm SM, Eisen AZ, Marmer BL, Grant GA, Seltzer JL, Kronberger A, He CS, Bauer EA, Goldberg GI: H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. J Biol Chem 1988;263:6579–6587.
[PubMed]
28.
Saus J, Quinones S, Otani Y, Nagase H, Harris ED Jr, Kurkinen M: The complete primary structure of human matrix metalloproteinase-3. Identity with stromelysin. J Biol Chem 1988;263:6742–6745.
[PubMed]
29.
Opbroek A, Kenney MC, Brown D: Characterization of a human corneal metalloproteinase inhibitor (TIMP-1). Curr Eye Res 1993;12:877–883.
30.
Stetler-Stevenson WG, Brown PD, Onisto M, Levy AT, Liotta LA: Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J Biol Chem 1990;265:13933–13938.
[PubMed]
31.
Kurokawa T, Sasada R, Iwane M, Igarashi K: Cloning and expression of cDNA encoding human basic fibroblast growth factor. FEBS Lett 1987;213:189–194.
[PubMed]
32.
Dignam JP, Lebovitz RM, Roeder RG: Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 1983;11:1475–1489.
[PubMed]
33.
Ramos-DeSimone N, Hahn-Dantona E, Sipley J, Nagase H, French DL, Quigley JP: Activation of matrix metalloproteinase-9 (MMP-9) via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion. J Biol Chem 1999;274:13066–13076.
[PubMed]
34.
Ahmad M, Theofanidis P, Medford RM: Role of activating protein-1 in the regulation of the vascular cell adhesion molecule-1 gene expression by tumor necrosis factor-alpha. J Biol Chem 1998;273:4616–4621.
[PubMed]
35.
Mohan R, Sivak J, Ashton P, Russo LA, Pham BQ, Kasahara N, Raizman MB, Fini ME: Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B J Biol Chem 2000;275:10405–10412.
36.
Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR: PD098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 1995;270:27489–27494.
[PubMed]
37.
Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM: Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 1998;273:18623–18632.
[PubMed]
38.
Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR, Lee JC: SB203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Letters 1995;364:229–233.
[PubMed]
39.
Rifkin DB, Moscatelli D: Recent developments in the cell biology of basic fibroblast growth factor. J Cell Biol 1998;109:1–6.
40.
Okada-Ban M, Thiery JP, Jouanneau J: Fibroblast growth factor-2. Int J Biochem Cell Biol 2000;32:263–267.
[PubMed]
41.
Thorn M, Raab Y, Larsson A, Gerdin B, Hallgren R: Intestinal mucosal secretion of basic fibroblast growth factor in patients with ulcerative colitis. Scand J Gastroenterol 2000;35:408–412.
[PubMed]
42.
Yao PM, Maitre B, Delacourt C, Buhler JM, Harf A, Lafuma C: Divergent regulation of 92-kD gelatinase and TIMP-1 by HBECs in response to IL-1β and TNF-α. Am J Physiol 1997;273:L866–874.
43.
Liu JF, Crepin M, Liu JM, Barritault D, Ledoux D: FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway. Biochem Biophys Res Commun 2002;293:1174–1182.
44.
Price SJ, Greaves DR, Watkins H: Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: Role of Sp1 in allele-specific transcriptional regulation. J Biol Chem 2001;276:7549–7558.
45.
Aho S, Rouda S, Kennedy SH, Qin H, Tan EML: Regulation of human interstitial collagenase (matrix metalloproteinase-1) promoter activity by fibroblast growth factor. Eur J Biochem 1997;247:503–510.
[PubMed]
46.
Kirstein M, Sanz L, Quinones S, Moscat J, Diaz-Meco MT, Saus J: Cross-talk between different enhancer elements during mitogenic induction of the human stromelysin-1 gene. J Biol Chem 1996;271:18231–18236.
[PubMed]
47.
Jaworski J, Biedermann IW, Lapinska J, Szklarczyk A, Figiel I, Konopka D, Nowicka D, Filipkowski RK, Hetman M, Kowalczyk A, Kaczmarek L: Neuronal excitation-driven and AP-1-dependent activation of tissue inhibitor of metalloproteinases-1 gene expression in rodent hippocampus. J Biol Chem 1999;274:28106–28112.
48.
Has SS, Keum YS, Seo HJ, Surth YJ: Curcumin suppresses activation of NF-κB and AP-1 induced by phorbol ester in human cultured promyelocytic leukemia cells. J Biochem Mol Biol 2002;35:337–342.
49.
Minden A, Karin M: Regulation and function of the JNK subgroup of MAP kinases. Biochim Biophys Acta 1997;1333:F85–104.
50.
Cobb MH, Goldsmith EJ: How MAP kinases are regulated. J Biol Chem 1995;270:14843–14846.
[PubMed]
51.
Han J, Lee JD, Bibbs L, Ulevitch RJ: A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 1994;265:808–811.
[PubMed]
52.
Chikazu D, Hakeda Y, Ogata N, Nemoto K, Itabashi A, Takato T, Kumegawa M, Nakamura K, Kawaguchi H: Fibroblast growth factor (FGF)-2 directly stimulates mature osteoclast function through activation of FGF receptor 1 and p42/p44 MAP kinase. J Biol Chem 2000;275:31444–31450.
53.
Shimazu A, Morishita M: Basic fibroblast growth factor induces the expression of matrix metalloproteinase-3 in human periodontal ligament cells through the MEK2 mitogen-activated protein kinase pathway. J Periodontal Res 2003;38:122–129.
54.
Kawano H, Kim S, Ohta K, Nakao T, Miyazaki H, Nakatani T, Iwao H: Differential contribution of three mitogen-activated protein kinases to PDGF-BB-induced mesangial cell proliferation and gene expression. J Am Soc Nephrol 2003;14:584–592.
55.
Li J, Ma C, Huang Y, Luo J, Huang C: Differential requirement of EGF receptor and its tyrosine kinase for AP-1 transactivation induced by EGF and TPA. Oncogene 2003;22:211–219.
56.
Bamba S, Andoh A, Yasui H, Makino J, Kim S, Fujiyama Y: Regulation of IL-11 expression in intestinal myofibroblasts: Role of c-Jun AP-1- and MAPK-dependent pathways. Am J Physiol 2003;285:G529–G538.
57.
Karin M, Liu Z, Zandi E: AP-1 function and regulation. Curr Opin Cell Biol 1997;9:240–246.
[PubMed]
58.
Angel P, Karin M: The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1991;1072:129–157.
[PubMed]
59.
Hsu JC, Cressman DE, Taub R: Promoter-specific trans-activation and inhibition mediated by JunB. Cancer Res 1993;53:3789–3794.
[PubMed]
You do not currently have access to this content.