Michael B. Dwinell, PhD
Associate Professor
Microbiology and Molecular Genetics
Medical College of Wisconsin
Research Focus: Mucosal Immunity; Immune Regulation in Cancer; Microbial Pathogenesis
PhD: University of Wisconsin, Madison (1996) Gastrointestinal Pathophysiology
Postdoctoral Training: University of California, San Diego; Mucosal Immunology |
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The Laboratory of Mucosal Immunology utilizes molecular, biochemical, cellular and genetic approaches in combination with human in vitro cell culture and murine in vivo model systems to: define innate immune responses at mucosal surfaces, explore the mechanisms by which those responses are regulated, and determine means by which those responses can be specifically manipulated. These studies are relevant to understanding disease pathogenesis of the inflammatory bowel diseases, colorectal cancer, as well as to gastrointestinal infections with disease causing food- and water-borne microbial pathogens. Our work is based on the hypothesis that immune molecules at the epithelial surface regulate the formation, maintenance and repair of the healthy mucosal barrier.
The cells of the intestinal epithelium constitute an essential component of the mucosal immune system forming a dynamic physical barrier to prevent or limit entry of potentially noxious stimuli (Model). The intestinal epithelium can become damaged by enteric pathogens or upon excessive stimulation with mucosal inflammatory mediators including cytokines, chemokines, and reactive oxygen metabolites (red arrow). Cytokines and chemokines within the intestinal mucosa are critical for effective inflammation and host defense and also bind and activate their receptors to regulate homeostatic growth and differentiation or initiate repair processes needed for a healthy mucosal barrier (green arrow). Epithelial maintenance and repair processes become dysregulated during neoplasia and transformation into colorectal tumors leading to disorganization of the epithelial innate barrier (yellow arrow).
Research projects in my lab include:
- Innate Immune Barrier Repair. We are investigating the impact of chemokines on maintenance and repair of the epithelial barrier. We are using human model intestinal epithelia and transgenic murine models to expand the paradigm that chemokines solely regulate leukocyte cell trafficking and show for the first time that a battery of chemokines can regulate mucosal wound healing and epithelial repair processes necessary for gastrointestinal innate immune defense.
- Chemokines in Cancer. These studies seek to define a role for chemokines in dysregulation of the innate immune barrier, tumor metastasis and carcinogenesis. Cancer of the human colon clearly represents a failure in normal homeostatic epithelial growth and differentiation. We are using human carcinoma cell lines as well as murine models of cancer to define the molecular events regulating transcription of chemokine genes and the functional impact of chemokines in tumor neoplasia and metastasis.
- Innate Defense against Pathogens. Our investigations are delineating innate immune responses of epithelial cells infected by microbial pathogens. Enteric pathogens utilize a number of different host colonization strategies, with interactions at the intestinal epithelium being the common pathogenic feature. Our studies are defining the cellular and biochemical mechanisms epithelial cells utilize to limit disease following infection by food- or water-borne microbes.
Recent Publications
Wendt, M.K., A.N. Cooper, and M.B. Dwinell. 2007. Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. Oncogene. 2007 Sep 3; [Epub ahead of print]
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Moyer RA, Wendt MK, Johanesen PA, Turner JR, Dwinell MB. Rho activation regulates CXCL12 chemokine stimulated actin rearrangement and restitution in model intestinal epithelia. Lab Invest. 2007 Aug;87(8):807-17. Epub 2007 Jun 18.
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Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MB. Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene. 2006 Aug 17;25(36):4986-97. Epub 2006 Mar 27.
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Johanesen PA, Dwinell MB. Flagellin-independent regulation of chemokine host defense in Campylobacter jejuni-infected intestinal epithelium. Infect Immun. 2006 Jun;74(6):3437-47.
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Binion DG, Kugathasan S, Dwinell MB. Molecular stratification of Crohn's disease by chemokine receptors: fractalkine receptor polymorphisms define a fibrostenosing ileal subgroup. Am J Gastroenterol. 2006 Jan;101(1):107-9.
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Yang CC, Ogawa H, Dwinell MB, McCole DF, Eckmann L, Kagnoff MF. The Chemokine Receptor CCR6 Transduces Signals that Activate p130Cas and Alter cAMP-Stimulated Ion Transport in Human Intestinal Epithelial Cells. Am J Physiol Cell Physiol. 2005 Feb;288(2):C321-8. Epub 2004 Oct 13.
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Smith JM, Johanesen PA, Wendt MK, Binion DG, Dwinell MB. CXCL12 activation of CXCR4 regulates mucosal host defense through stimulation of epithelial cell migration and promotion of intestinal barrier integrity. Am J Physiol Gastrointest Liver Physiol. 2005 Feb;288(2):G316-26. Epub 2004 Sep 9.
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Heidemann J, Ogawa H, Rafiee P, Lugering N, Maaser C, Domschke W, Binion DG, Dwinell MB. Mucosal angiogenesis regulation by CXCR4 and its ligand CXCL12 expressed by human intestinal microvascular endothelial cells. Am J Physiol Gastrointest Liver Physiol. 2004 Jun;286(6):G1059-68. Epub 2004 Feb 05.
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Dwinell MB, Ogawa H, Barrett KE, Kagnoff MF. SDF-1/CXCL12 regulates cAMP production and ion transport in intestinal epithelial cells via CXCR4. Am J Physiol Gastrointest Liver Physiol. 2004 May;286(5):G844-50. Epub 2003 Dec 18.
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Rafiee P, Ogawa H, Heidemann J, Li MS, Aslam M, Lamirand TH, Fisher PJ, Graewin SJ, Dwinell MB, Johnson CP, Shaker R, Binion DG. Isolation and characterization of human esophageal microvascular endothelial cells: mechanisms of inflammatory activation. Am J Physiol Gastrointest Liver Physiol. 2003 Dec;285(6):G1277-92. Epub 2003 Aug 14.
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Dwinell MB, Johanesen PA, Smith JM. Immunobiology of epithelial chemokines in the intestinal mucosa. Surgery. 2003 Jun;133(6):601-7. Review.
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Heidemann J, Ogawa H, Dwinell MB, Rafiee P, Maaser C, Gockel HR, Otterson MF, Ota DM, Lugering N, Domschke W, Binion DG. Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem. 2003 Mar 7;278(10):8508-15. Epub 2002 Dec 20.
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Berin MC, Dwinell MB, Eckmann L, Kagnoff MF. Production of MDC/CCL22 by human intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2001 Jun;280(6):G1217-26.
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Izadpanah A, Dwinell MB, Eckmann L, Varki NM, Kagnoff MF. Regulated MIP-3alpha/CCL20 production by human intestinal epithelium: mechanism for modulating mucosal immunity. Am J Physiol Gastrointest Liver Physiol. 2001 Apr;280(4):G710-9.
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Dwinell MB, Lugering N, Eckmann L, Kagnoff MF. Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells. Gastroenterology. 2001 Jan;120(1):49-59.
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Eckmann L, Smith JR, Housley MP, Dwinell MB, Kagnoff MF. Analysis by high density cDNA arrays of altered gene expression in human intestinal epithelial cells in response to infection with the invasive enteric bacteria Salmonella. J Biol Chem. 2000 May 12;275(19):14084-94.
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Merendino N, Dwinell MB, Varki N, Eckmann L, Kagnoff MF. Human intestinal epithelial cells express receptors for platelet-activating factor. Am J Physiol. 1999 Oct;277(4 Pt 1):G810-8.
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Dwinell MB, Eckmann L, Leopard JD, Varki NM, Kagnoff MF. Chemokine receptor expression by human intestinal epithelial cells. Gastroenterology. 1999 Aug;117(2):359-67.
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Contact Information
Email: mdwinell@mcw.edu
Phone: 414-456-7427
Room: BSB-208