Increased levels of the matrix metalloproteinases-2 and -9 (also referred to gelatinase-A and -B, respectively) can be detected in intestinal inflammation. We have recently shown that selective gelatinase blockage by the synthetic compound RO28-2653 ameliorates acute murine ileitis and colitis. We here investigated whether RO28-2653 exerts anti-inflammatory effects in acute Campylobacter jejuni-induced enterocolitis of gnotobiotic IL-10−/− mice generated following antibiotic treatment. Mice were perorally infected with C. jejuni (day 0) and either treated with RO28-2653 (75 mg/kg body weight/day) or placebo from day 1 until day 6 post infection (p.i.) by gavage. Irrespective of the treatment, infected mice displayed comparable pathogen loads within the gastrointestinal tract. Following RO28-2653 administration, however, infected mice exhibited less severe symptoms such as bloody diarrhea as compared to placebo controls. Furthermore, less distinct apoptosis but higher numbers of proliferating cells could be detected in the colon of RO28-2653-treated as compared to placebo-treated mice at day 7 p.i. Remarkably, gelatinase blockage resulted in lower numbers of T- and B-lymphocytes as well as macrophages and monocytes in the colonic mucosa of C. jejuni-infected gnotobiotic IL-10−/− mice. Taken together, synthetic gelatinase inhibition exerts anti-inflammatory effects in experimental campylobacteriosis.
Hermans D, Pasmans F, Messens W, Martel A, Van Immerseel F, et al.: Poultry as a host for the zoonotic pathogen Campylobacter jejuni. Vector Borne Zoonotic Dis 12, 89–98 (2012)
Immerseel F , 'Poultry as a host for the zoonotic pathogen Campylobacter jejuni ' (2012 ) 12 Vector Borne Zoonotic Dis : 89 -98 .
Man SM: The clinical importance of emerging Campylobacter species. Nat Rev Gastroenterol Hepatol 8, 669–685 (2011)
Man SM , 'The clinical importance of emerging Campylobacter species ' (2011 ) 8 Nat Rev Gastroenterol Hepatol : 669 -685 .
Lane JA, Mehra RK, Carrington SD, Hickey RM: The food glycome: a source of protection against pathogen colonization in the gastrointestinal tract. Int J Food Microbiol 142, 1–13 (2010)
Hickey RM , 'The food glycome: a source of protection against pathogen colonization in the gastrointestinal tract ' (2010 ) 142 Int J Food Microbiol : 1 -13 .
Guerry P, Szymanski CM: Campylobacter sugars sticking out. Trends Microbiol 16, 428–435 (2008)
Szymanski CM , 'Campylobacter sugars sticking out ' (2008 ) 16 Trends Microbiol : 428 -435 .
Kist M, Bereswill S: Campylobacter jejuni. Contrib Microbiol 8, 150–165 (2001)
Bereswill S , 'Campylobacter jejuni ' (2001 ) 8 Contrib Microbiol : 150 -165 .
Havelaar AH, van Pelt W, Ang CW, Wagenaar JA, van Putten JP, et al.: Immunity to Campylobacter: its role in risk assessment and epidemiology. Crit Rev Microbiol 35, 1–22 (2009)
Putten JP , 'Immunity to Campylobacter: its role in risk assessment and epidemiology ' (2009 ) 35 Crit Rev Microbiol : 1 -22 .
Janssen R, Krogfelt KA, Cawthraw SA, van Pelt W, Wagenaar JA, et al.: Host-pathogen interactions in Campylobacter infections: the host perspective. Clin Microbiol Rev 21, 505–518 (2008)
Wagenaar JA , 'Host-pathogen interactions in Campylobacter infections: the host perspective ' (2008 ) 21 Clin Microbiol Rev : 505 -518 .
van Spreeuwel JP, Duursma GC, Meijer CJ, Bax R, Rosekrans PC, et al.: Campylobacter colitis: histological immunohistochemical and ultrastructural findings. Gut 26, 945–951 (1985)
Rosekrans PC , 'Campylobacter colitis: histological immunohistochemical and ultrastructural findings ' (1985 ) 26 Gut : 945 -951 .
Walker RI, Caldwell MB, Lee EC, Guerry P, Trust TJ, et al.: Pathophysiology of Campylobacter enteritis. Microbiol Rev 50, 81–94 (1986)
Trust TJ , 'Pathophysiology of Campylobacter enteritis ' (1986 ) 50 Microbiol Rev : 81 -94 .
Haag LM, Fischer A, Otto B, Plickert R, Kuhl AA, et al.: Campylobacter jejuni induces acute enterocolitis in gnotobiotic IL-10−/− mice via Toll-like-receptor-2 and-4 signaling. PLoS One 7, e40761 (2012)
Kuhl AA , 'Campylobacter jejuni induces acute enterocolitis in gnotobiotic IL-10−/− mice via Toll-like-receptor-2 and-4 signaling ' (2012 ) 7 PLoS One : 40761 -.
Heimesaat MM, Lugert R, Fischer A, Alutis M, Kuhl AA, et al.: Impact of Campylobacter jejuni cj0268c knockout mutation on intestinal colonization, translocation, and induction of immunopathology in gnotobiotic IL-10 deficient mice. PLoS One 9, e90148 (2014)
Kuhl AA , 'Impact of Campylobacter jejuni cj0268c knockout mutation on intestinal colonization, translocation, and induction of immunopathology in gnotobiotic IL-10 deficient mice ' (2014 ) 9 PLoS One : 90148 -.
Heimesaat MM, Alutis M, Grundmann U, Fischer A, Tegtmeyer N, et al.: The role of serine protease HtrA in acute ulcerative enterocolitis and extra-intestinal immune responses during Campylobacter jejuni infection of gnotobiotic IL-10 deficient mice. Front Cell Infect Microbiol 4, 77 (2014)
Tegtmeyer N , 'The role of serine protease HtrA in acute ulcerative enterocolitis and extra-intestinal immune responses during Campylobacter jejuni infection of gnotobiotic IL-10 deficient mice ' (2014 ) 4 Front Cell Infect Microbiol : 77 -.
Warren HS, Fitting C, Hoff E, Adib-Conquy M, Beasley-Topliffe L, et al.: Resilience to bacterial infection: difference between species could be due to proteins in serum. J Infect Dis 201, 223–232 (2010)
Beasley-Topliffe L , 'Resilience to bacterial infection: difference between species could be due to proteins in serum ' (2010 ) 201 J Infect Dis : 223 -232 .
Masanta WO, Heimesaat MM, Bereswill S, Tareen AM, Lugert R, et al.: Modification of intestinal microbiota and its consequences for innate immune response in the pathogenesis of Campylobacteriosis. Clin Dev Immunol, 526860 (2013)
Lugert R , '', in Clin Dev Immunol , (2013 ) -.
Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, et al.: Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4, 197–250 (1993)
Birkedal-Hansen B , 'Matrix metalloproteinases: a review ' (1993 ) 4 Crit Rev Oral Biol Med : 197 -250 .
Brinckerhoff CE, Matrisian LM: Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 3, 207–214 (2002)
Matrisian LM , 'Matrix metalloproteinases: a tail of a frog that became a prince ' (2002 ) 3 Nat Rev Mol Cell Biol : 207 -214 .
Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM: Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 18, 1135–1149 (2000)
Matrisian LM , 'Matrix metalloproteinases: biologic activity and clinical implications ' (2000 ) 18 J Clin Oncol : 1135 -1149 .
Goetzl EJ, Banda MJ, Leppert D: Matrix metalloproteinases in immunity. J Immunol 156, 1–4 (1996)
Leppert D , 'Matrix metalloproteinases in immunity ' (1996 ) 156 J Immunol : 1 -4 .
Crawford HC, Matrisian LM: Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells. Enzyme Protein 49, 20–37 (1996)
Matrisian LM , 'Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells ' (1996 ) 49 Enzyme Protein : 20 -37 .
Saren P, Welgus HG, Kovanen PT: TNF-alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol 157, 4159–4165 (1996)
Kovanen PT , 'TNF-alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages ' (1996 ) 157 J Immunol : 4159 -4165 .
Salmela MT, MacDonald TT, Black D, Irvine B, Zhuma T, et al.: Upregulation of matrix metalloproteinases in a model of T cell mediated tissue injury in the gut: analysis by gene array and in situ hybridisation. Gut 51, 540–547 (2002)
Zhuma T , 'Upregulation of matrix metalloproteinases in a model of T cell mediated tissue injury in the gut: analysis by gene array and in situ hybridisation ' (2002 ) 51 Gut : 540 -547 .
Munoz M, Heimesaat MM, Danker K, Struck D, Lohmann U, et al.: Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetallo-proteinase-2 and IL-22 but independent of IL-17. J Exp Med 206, 3047–3059 (2009)
Lohmann U , 'Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetallo-proteinase-2 and IL-22 but independent of IL-17 ' (2009 ) 206 J Exp Med : 3047 -3059 .
Heimesaat MM, Dunay IR, Fuchs D, Trautmann D, Fischer A, et al.: Selective gelatinase blockage ameliorates acute DSS colitis. Eur J Microbiol Immunol (Bp) 1, 228–236 (2011)
Fischer A , 'Selective gelatinase blockage ameliorates acute DSS colitis ' (2011 ) 1 Eur J Microbiol Immunol (Bp) : 228 -236 .
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 47, 63–73 (2000)
Rosewicz S , 'Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease ' (2000 ) 47 Gut : 63 -73 .
Bailey CJ, Hembry RM, Alexander A, Irving MH, Grant ME, et al.: Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn’s disease and normal intestine. J Clin Pathol 47, 113–116 (1994)
Grant ME , 'Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn’s disease and normal intestine ' (1994 ) 47 J Clin Pathol : 113 -116 .
Baugh MD, Perry MJ, Hollander AP, Davies DR, Cross SS, et al.: Matrix metalloproteinase levels are elevated in inflammatory bowel disease. Gastroenterology 117, 814–822 (1999)
Cross SS , 'Matrix metalloproteinase levels are elevated in inflammatory bowel disease ' (1999 ) 117 Gastroenterology : 814 -822 .
Lein M, Jung K, Ortel B, Stephan C, Rothaug W, et al.: The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model. Oncogene 21, 2089–2096 (2002)
Rothaug W , 'The new synthetic matrix metalloproteinase inhibitor (Roche 28-2653) reduces tumor growth and prolongs survival in a prostate cancer standard rat model ' (2002 ) 21 Oncogene : 2089 -2096 .
Bernardo MM, Brown S, Li ZH, Fridman R, Mobashery S: Design, synthesis, and characterization of potent, slowbinding inhibitors that are selective for gelatinases. J Biol Chem 277, 11201–11207 (2002)
Mobashery S , 'Design, synthesis, and characterization of potent, slowbinding inhibitors that are selective for gelatinases ' (2002 ) 277 J Biol Chem : 11201 -11207 .
Heimesaat MM, Bereswill S, Fischer A, Fuchs D, Struck D, et al.: Gram-negative bacteria aggravate murine small in testinal Th1-type immunopathology following oral infection with Toxoplasma gondii. J Immunol 177, 8785–8795 (2006)
Struck D , 'Gram-negative bacteria aggravate murine small in testinal Th1-type immunopathology following oral infection with Toxoplasma gondii ' (2006 ) 177 J Immunol : 8785 -8795 .
Bereswill S, Munoz M, Fischer A, Plickert R, Haag LM, et al.: Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation. PLoS One 5, e15099 (2010)
Haag LM , 'Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation ' (2010 ) 5 PLoS One : 15099 -.
Haag LM, Fischer A, Otto B, Plickert R, Kuhl AA, et al.: Intestinal microbiota shifts towards elevated commensal Escherichia coli loads abrogate colonization resistance against Campylobacter jejuni in mice. PLoS One 7, e35988 (2012)
Kuhl AA , 'Intestinal microbiota shifts towards elevated commensal Escherichia coli loads abrogate colonization resistance against Campylobacter jejuni in mice ' (2012 ) 7 PLoS One : 35988 -.
Heimesaat MM, Nogai A, Bereswill S, Plickert R, Fischer A, et al.: MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut 59, 1079–1087 (2010)
Fischer A , 'MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease ' (2010 ) 59 Gut : 1079 -1087 .
Bereswill S, Fischer A, Plickert R, Haag LM, Otto B, et al.: Novel murine infection models provide deep insights into the “Menage a Trois” of Campylobacter jejuni, Microbiota and host innate immunity. PLoS One 6, e20953 (2011)
Otto B , 'Novel murine infection models provide deep insights into the “Menage a Trois” of Campylobacter jejuni, Microbiota and host innate immunity ' (2011 ) 6 PLoS One : 20953 -.
Heimesaat MM, Haag LM, Fischer A, Otto B, Kuhl AA, et al.: Survey of extra-intestinal immune responses in asymptomatic long-term Campylobacter jejuni-infected mice. Eur J Microbiol Immunol (Bp) 3, 174–182 (2013)
Kuhl AA , 'Survey of extra-intestinal immune responses in asymptomatic long-term Campylobacter jejuni-infected mice ' (2013 ) 3 Eur J Microbiol Immunol (Bp) : 174 -182 .
Haag LM, Fischer A, Otto B, Grundmann U, Kuhl AA, et al.: Campylobacter jejuni infection of infant mice: acute enterocolitis is followed by asymptomatic intestinal and extra-intestinal immune responses. Eur J Microbiol Immunol (Bp) 2, 2–11 (2012)
Kuhl AA , 'Campylobacter jejuni infection of infant mice: acute enterocolitis is followed by asymptomatic intestinal and extra-intestinal immune responses ' (2012 ) 2 Eur J Microbiol Immunol (Bp) : 2 -11 .
Naito Y, Takagi T, Kuroda M, Katada K, Ichikawa H, et al.: An orally active matrix metalloproteinase inhibitor, ONO-4817, reduces dextran sulfate sodium-induced colitis in mice. Inflamm Res 53, 462–468 (2004)
Ichikawa H , 'An orally active matrix metalloproteinase inhibitor, ONO-4817, reduces dextran sulfate sodium-induced colitis in mice ' (2004 ) 53 Inflamm Res : 462 -468 .
Parks WC, Lopez-Boado YS, Wilson CL: Matrilysin in epithelial repair and defense. Chest 120, 36S–41S (2001)
Wilson CL , 'Matrilysin in epithelial repair and defense ' (2001 ) 120 Chest : 36S -41S .
Wang M, Qin X, Mudgett JS, Ferguson TA, Senior RM, et al.: Matrix metalloproteinase deficiencies affect contact hypersensitivity: stromelysin-1 deficiency prevents the response and gelatinase B deficiency prolongs the response. Proc Natl Acad Sci U S A 96, 6885–6889 (1999)
Senior RM , 'Matrix metalloproteinase deficiencies affect contact hypersensitivity: stromelysin-1 deficiency prevents the response and gelatinase B deficiency prolongs the response ' (1999 ) 96 Proc Natl Acad Sci U S A : 6885 -6889 .