Matrix metalloproteinase-19 (MMP19) affects cell proliferation, adhesion, and migration in vitro but its physiological role in vivo is poorly understood. To determine the function of MMP19, we generated mice deficient for MMP19 by disrupting the catalytic domain of mmp19 gene. Although MMP19-deficient mice do not show overt developmental and morphological abnormalities they display a distinct physiological phenotype. In a model of contact hypersensitivity (CHS) MMP19-deficient mice showed impaired T cell-mediated immune reaction that was characterized by limited influx of inflammatory cells, low proliferation of keratinocytes, and reduced number of activated CD8(+) T cells in draining lymph nodes. In the inflamed tissue, the low number of CD8(+) T cells in MMP19-deficient mice correlated with low amounts of proinflammatory cytokines, especially lymphotactin and interferon-inducible T cell alpha chemoattractant (I-TAC). Further analyses showed that T cell populations in the blood of immature, unsensitized mice were diminished and that this alteration originated from an altered maturation of thymocytes. In the thymus, thymocytes exhibited low proliferation rates and the number of CD4(+)CD8(+) double-positive cells was remarkably augmented. Based on the phenotype of MMP19-deficient mice we propose that MMP19 is an important factor in cutaneous immune responses and influences the development of T cells.

Institute of Biotechnology Prague Czech Republic

Zobrazit více v PubMed

Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nature reviews. 2007;8:221–233. PubMed PMC

Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–867. PubMed PMC

Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69:562–573. PubMed

Sedlacek R, Mauch S, Kolb B, Schatzlein C, Eibel H, et al. Matrix metalloproteinase MMP-19 (RASI-1) is expressed on the surface of activated peripheral blood mononuclear cells and is detected as an autoantigen in rheumatoid arthritis. Immunobiology. 1998;198:408–23. PubMed

Cossins J, Dudgeon TJ, Catlin G, Gearing AJ, Clements JM. Identification of MMP-18, a putative novel human matrix metalloproteinase. Biochem Biophys Res Commun. 1996;228:494–8. PubMed

Pendas AM, Knauper V, Puente XS, Llano E, Mattei MG, et al. Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution. J Biol Chem. 1997;272:4281–4286. PubMed

Mueller MS, Harnasch M, Kolb C, Kusch J, Sadowski T, et al. The murine ortholog of matrix metalloproteinase 19: its cloning, gene organization, and expression. Gene. 2000;256:101–111. PubMed

Mueller MS, Mauch S, Sedlacek R. Structure of the human MMP-19 gene. Gene. 2000 Jul 11; 252(1–2):27–37. PubMed

Stracke JO, Fosang AJ, Last K, Mercuri FA, Pendas AM, et al. Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP). FEBS Lett. 2000 Jul 28; 478(1–2):52–6. PubMed

Kolb C, Mauch S, Peter HH, Krawinkel U, Sedlacek R. The matrix metalloproteinase RASI-1 is expressed in synovial blood vessels of a rheumatoid arthritis patient. Immunol Lett. 1997;57:83–88. PubMed

Kolb C, Mauch S, Krawinkel U, Sedlacek R. Matrix metalloproteinase-19 in capillary endothelial cells: expression in acutely, but not in chronically, inflamed synovium. Exp Cell Res. 1999;250:122–130. PubMed

Djonov V, Hogger K, Sedlacek R, Laissue J, Draeger A. MMP-19: cellular localization of a novel metalloproteinase within normal breast tissue and mammary gland tumours. J Pathol. 2001;195:147–155. PubMed

Sadowski T, Dietrich S, Muller M, Havlickova B, Schunck M, et al. Matrix metalloproteinase-19 expression in normal and diseased skin: dysregulation by epidermal proliferation. J Invest Dermatol. 2003;121:989–996. PubMed

Sadowski T, Dietrich S, Koschinsky F, Sedlacek R. Matrix metalloproteinase 19 regulates insulin-like growth factor-mediated proliferation, migration, and adhesion in human keratinocytes through proteolysis of insulin-like growth factor binding protein-3. Mol Biol Cell. 2003;14:4569–4580. PubMed PMC

Mauch S, Kolb C, Kolb B, Sadowski T, Sedlacek R. Matrix metalloproteinase-19 is expressed in myeloid cells in an adhesion-dependent manner and associates with the cell surface. J Immunol. 2002;168:1244–1251. PubMed

Sadowski T, Dietrich S, Koschinsky F, Ludwig A, Proksch E, et al. Matrix metalloproteinase 19 processes the laminin 5 gamma 2 chain and induces epithelial cell migration. Cell Mol Life Sci. 2005;62:870–880. PubMed PMC

Titz B, Dietrich S, Sadowski T, Beck C, Petersen A, et al. Activity of MMP-19 inhibits capillary-like formation due to processing of nidogen-1. Cell Mol Life Sci. 2004;61:1826–1833. PubMed PMC

Stracke JO, Hutton M, Stewart M, Pendas AM, Smith B, et al. Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19. Evidence for a role as a potent basement membrane degrading enzyme. J Biol Chem. 2000;275:14809–14816. PubMed

van Horssen J, Vos CM, Admiraal L, van Haastert ES, Montagne L, et al. Matrix metalloproteinase-19 is highly expressed in active multiple sclerosis lesions. Neuropathology and applied neurobiology. 2006;32:585–593. PubMed

Behera AK, Hildebrand E, Scagliotti J, Steere AC, Hu LT. Induction of host matrix metalloproteinases by Borrelia burgdorferi differs in human and murine lyme arthritis. Infect Immun. 2005;73:126–134. PubMed PMC

Locati M, Deuschle U, Massardi ML, Martinez FO, Sironi M, et al. Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes. J Immunol. 2002;168:3557–3562. PubMed

Ramanathan M, Weinstock-Guttman B, Nguyen LT, Badgett D, Miller C, et al. In vivo gene expression revealed by cDNA arrays: the pattern in relapsing-remitting multiple sclerosis patients compared with normal subjects. J Neuroimmunol. 2001;116:213–219. PubMed

Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. 2004;4:617–629. PubMed

Cavani A, Albanesi C, Traidl C, Sebastiani S, Girolomoni G. Effector and regulatory T cells in allergic contact dermatitis. Trends Immunol. 2001;22:118–120. PubMed

Grabbe S, Schwarz T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol Today. 1998;19:37–44. PubMed

Wang B, Fujisawa H, Zhuang L, Freed I, Howell BG, et al. CD4+ Th1 and CD8+ type 1 cytotoxic T cells both play a crucial role in the full development of contact hypersensitivity. J Immunol. 2000;165:6783–6790. PubMed

Bouloc A, Cavani A, Katz SI. Contact hypersensitivity in MHC class II-deficient mice depends on CD8 T lymphocytes primed by immunostimulating Langerhans cells. J Invest Dermatol. 1998;111:44–49. PubMed

Bour H, Peyron E, Gaucherand M, Garrigue JL, Desvignes C, et al. Major histocompatibility complex class I-restricted CD8+ T cells and class II-restricted CD4+ T cells, respectively, mediate and regulate contact sensitivity to dinitrofluorobenzene. Eur J Immunol. 1995;25:3006–3010. PubMed

Gocinski BL, Tigelaar RE. Roles of CD4+ and CD8+ T cells in murine contact sensitivity revealed by in vivo monoclonal antibody depletion. J Immunol. 1990;144:4121–4128. PubMed

Akiba H, Kehren J, Ducluzeau MT, Krasteva M, Horand F, et al. Skin inflammation during contact hypersensitivity is mediated by early recruitment of CD8+ T cytotoxic 1 cells inducing keratinocyte apoptosis. J Immunol. 2002;168:3079–3087. PubMed

Xu H, DiIulio NA, Fairchild RL. T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: interferon gamma-producing (Tc1) effector CD8+ T cells and interleukin (Il) 4/Il-10-producing (Th2) negative regulatory CD4+ T cells. J Exp Med. 1996;183:1001–1012. PubMed PMC

Gorbachev AV, Fairchild RL. Regulatory role of CD4+ T cells during the development of contact hypersensitivity responses. Immunol Res. 2001;24:69–77. PubMed

Lopez CB, Kalergis AM, Becker MI, Garbarino JA, De Ioannes AE. CD8+ T cells are the effectors of the contact dermatitis induced by urushiol in mice and are regulated by CD4+ T cells. Int Arch Allergy Immunol. 1998;117:194–201. PubMed

Moodycliffe AM, Shreedhar V, Ullrich SE, Walterscheid J, Bucana C, et al. CD40-CD40 ligand interactions in vivo regulate migration of antigen-bearing dendritic cells from the skin to draining lymph nodes. J Exp Med. 2000;191:2011–2020. PubMed PMC

Mizumoto N, Iwabichi K, Nakamura H, Ato M, Shibaki A, et al. Enhanced contact hypersensitivity in human monocyte chemoattractant protein-1 transgenic mouse. Immunobiology. 2001;204:477–493. PubMed

Suto H, Nakae S, Kakurai M, Sedgwick JD, Tsai M, et al. Mast cell-associated TNF promotes dendritic cell migration. J Immunol. 2006;176:4102–4112. PubMed

Nakae S, Naruse-Nakajima C, Sudo K, Horai R, Asano M, et al. IL-1 alpha, but not IL-1 beta, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity. Int Immunol. 2001;13:1471–1478. PubMed

Nakae S, Komiyama Y, Narumi S, Sudo K, Horai R, et al. IL-1-induced tumor necrosis factor-alpha elicits inflammatory cell infiltration in the skin by inducing IFN-gamma-inducible protein 10 in the elicitation phase of the contact hypersensitivity response. Int Immunol. 2003;15:251–260. PubMed

Masuda K, Katoh N, Soga F, Kishimoto S. The role of interleukin-16 in murine contact hypersensitivity. Clinical and experimental immunology. 2005;140:213–219. PubMed PMC

Nakamura K, Williams IR, Kupper TS. Keratinocyte-derived monocyte chemoattractant protein 1 (MCP-1): analysis in a transgenic model demonstrates MCP-1 can recruit dendritic and Langerhans cells to skin. J Invest Dermatol. 1995;105:635–643. PubMed

Shimizu T, Abe R, Nishihira J, Shibaki A, Watanabe H, et al. Impaired contact hypersensitivity in macrophage migration inhibitory factor-deficient mice. Eur J Immunol. 2003;33:1478–1487. PubMed

Blachere NE, Morris HK, Braun D, Saklani H, Di Santo JP, et al. IL-2 is required for the activation of memory CD8+ T cells via antigen cross-presentation. J Immunol. 2006;176:7288–7300. PubMed

Mescher MF, Curtsinger JM, Agarwal P, Casey KA, Gerner M, et al. Signals required for programming effector and memory development by CD8+ T cells. Immunol Rev. 2006;211:81–92. PubMed

Dilulio NA, Engeman T, Armstrong D, Tannenbaum C, Hamilton TA, et al. Groalpha-mediated recruitment of neutrophils is required for elicitation of contact hypersensitivity. Eur J Immunol. 1999;29:3485–3495. PubMed

Goebeler M, Trautmann A, Voss A, Brocker EV, Toksoy A, et al. Differential and sequential expression of multiple chemokines during elicitation of allergic contact hypersensitivity. Am J Pathol. 2001;158:431–440. PubMed PMC

Piguet PF, Grau GE, Hauser C, Vassalli P. Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions. J Exp Med. 1991;173:673–679. PubMed PMC

Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 2006;203:2201–2213. PubMed PMC

Cole KE, Strick CA, Paradis TJ, Ogborne KT, Loetscher M, et al. Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J Exp Med. 1998;187:2009–2021. PubMed PMC

Mohan K, Cordeiro E, Vaci M, McMaster C, Issekutz TB. CXCR3 is required for migration to dermal inflammation by normal and in vivo activated T cells: differential requirements by CD4 and CD8 memory subsets. Eur J Immunol. 2005;35:1702–1711. PubMed

Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, et al. The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest. 1998;101:746–754. PubMed PMC

Sauty A, Colvin RA, Wagner L, Rochat S, Spertini F, et al. CXCR3 internalization following T cell-endothelial cell contact: preferential role of IFN-inducible T cell alpha chemoattractant (CXCL11). J Immunol. 2001;167:7084–7093. PubMed

Tensen CP, Flier J, Van Der Raaij-Helmer EM, Sampat-Sardjoepersad S, Van Der Schors RC, et al. Human IP-9: A keratinocyte-derived high affinity CXC-chemokine ligand for the IP-10/Mig receptor (CXCR3). J Invest Dermatol. 1999;112):716–722. PubMed

Kelner GS, Kennedy J, Bacon KB, Kleyensteuber S, Largaespada DA, et al. Lymphotactin: a cytokine that represents a new class of chemokine. Science. 1994;266:1395–1399. PubMed

Savino W, Mendes-da-Cruz DA, Silva JS, Dardenne M, Cotta-de-Almeida V. Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines? Trends Immunol. 2002;23:305–13. PubMed

Vivinus-Nebot M, Rousselle P, Breittmayer JP, Cenciarini C, Berrih-Aknin S, et al. Mature human thymocytes migrate on laminin-5 with activation of metalloproteinase-14 and cleavage of CD44. J Immunol. 2004;172:1397–1406. PubMed

Saint-Mezard P, Chavagnac C, Vocanson M, Kehren J, Rozieres A, et al. Deficient contact hypersensitivity reaction in CD4-/- mice is because of impaired hapten-specific CD8+ T cell functions. J Invest Dermatol. 2005;124:562–569. PubMed

Saint-Mezard P, Krasteva M, Chavagnac C, Bosset S, Akiba H, et al. Afferent and efferent phases of allergic contact dermatitis (ACD) can be induced after a single skin contact with haptens: evidence using a mouse model of primary ACD. The Journal of investigative dermatology. 2003;120:641–647. PubMed

Takeshita K, Yamasaki T, Akira S, Gantner F, Bacon KB. Essential role of MHC II-independent CD4+ T cells, IL-4 and STAT6 in contact hypersensitivity induced by fluorescein isothiocyanate in the mouse. International immunology. 2004;16:685–695. PubMed

Pendas AM, Folgueras AR, Llano E, Caterina J, Frerard F, et al. Diet-induced obesity and reduced skin cancer susceptibility in matrix metalloproteinase 19-deficient mice. Mol Cell Biol. 2004;24:5304–5313. PubMed PMC

Jost M, Folgueras AR, Frerart F, Pendas AM, Blacher S, et al. Earlier onset of tumoral angiogenesis in matrix metalloproteinase-19-deficient mice. Cancer Res. 2006;66:5234–5241. PubMed

Warner RL, Beltran L, Younkin EM, Lewis CS, Weiss SJ, et al. Role of stromelysin 1 and gelatinase B in experimental acute lung injury. Am J Respir Cell Mol Biol. 2001;24:537–544. PubMed

Warner RL, Lewis CS, Beltran L, Younkin EM, Varani J, et al. The role of metalloelastase in immune complex-induced acute lung injury. Am J Pathol. 2001;158:2139–2144. PubMed PMC

Hu J, Van den Steen PE, Sang QX, Opdenakker G. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov. 2007;6:480–498. PubMed

Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, et al. The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 2005;280:35760–35766. PubMed

Haidl ID, Falk I, Nerz G, Eichmann K. Metalloproteinase-dependent control of thymocyte differentiation and proliferation. Scand J Immunol. 2006;64:280–286. PubMed

Aoudjit F, Esteve PO, Desrosiers M, Potworowski EF, St-Pierre Y. Gelatinase B (MMP-9) production and expression by stromal cells in the normal and adult thymus and experimental thymic lymphoma. International journal of cancer. 1997;71:71–78. PubMed

Odaka C, Tanioka M, Itoh T. Matrix metalloproteinase-9 in macrophages induces thymic neovascularization following thymocyte apoptosis. J Immunol. 2005;174:846–853. PubMed

Schroen DJ, Cheung HT. Interaction of mouse thymocytes and a thymocyte-like cell line with the ECM glycoprotein entactin. Cellular immunology. 1996;167:141–149. PubMed

Van Lint P, Libert C. Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J Leukoc Biol. 2007;82:1375–1381. PubMed

Tybulewicz VL, Crawford CE, Jackson PK, Bronson RT, Mulligan RC. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991;65:1153–1163. PubMed

Hogan B, Beddington R, Constantini F, Lacy E. Oxford: Oxford University Press; 1994. Manipulating the mouse embryo, 2nd ed. p. 779.

Held-Feindt J, Paredes EB, Blomer U, Seidenbecher C, Stark AM, et al. Matrix-degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas. Int J Cancer. 2006;118:55–61. PubMed

Brandt K, Bulfone-Paus S, Jenckel A, Foster DC, Paus R, et al. Interleukin-21 inhibits dendritic cell-mediated T cell activation and induction of contact hypersensitivity in vivo. The Journal of investigative dermatology. 2003;121:1379–1382. PubMed

Macatonia SE, Edwards AJ, Knight SC. Dendritic cells and the initiation of contact sensitivity to fluorescein isothiocyanate. Immunology. 1986;59:509–514. PubMed PMC

Caldelari R, Suter MM, Baumann D, De Bruin A, Muller E. Long-term culture of murine epidermal keratinocytes. J Invest Dermatol. 2000;114:1064–1065. PubMed

MMP-19 deficiency causes aggravation of colitis due to defects in innate immune cell function

Hepatoprotective effect of MMP-19 deficiency in a mouse model of chronic liver fibrosis