James L. Madara, M.D.

Molecular Mechanisms of Pathogen Interactions with Polarized Epithelia, Neutrophil Interactions with Polarized Epithelia, and Junction Mediated Interactions Between Polarized Epithelia

Research Summary

I have always focused on the biology of polarized epithelial cells, largely using intestinal epithelia as a model. However, many of the findings we have reported have subsequently shown to hold for other polarized epithelia such as those in the airway, the kidney, etc. While focused early on in the subfields of transport and barrier function, our work in recent years has led to a focus on issues regarding innate immunity ­ how epithelial cells can coordinate inflammatory responses and, also recently, repress such responses. This has led, in parallel, to examination of what roles prokaryotes play in activation (and repression) of epithelial-orchestrated inflammatory responses.

Selected Papers

Si-Tahar M, Sitaraman S, Shibahara T, Madara JL. (2001). Negative regulation of epithelium-neutrophil interactions via activation of CD44. Am J Physiol Cell Physiol, 280(3):C423-C432.

Nusrat A, von Eichel-Streiber C, Turner JR, Verkade P, Madara JL, Parkos CS. (2001). Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect Immun, 69(3):1329-1336.

Merlin D, Lencer W, Selsted M, Madara JL. (2001). Cryptdin-3 induces novel apical conductance(s) in Cl- secretory, including cystic fibrosis, epithelia. Am J Physiol Cell Physiol, 280(2):C296-C302.

Reaves TA, Colgan SA, Selvaraj P, Walsh S, Nusrat A, Liang TW, Pochet MM, Madara JL, Parkos CA. (2001). Neutrophil transepithelial migration: regulation at the apical epithelial surface by Fc-mediated events. Amer J Physiol, 280(4):G746-G754.

Gewirtz AT, Simon PO, Jr., Schmitt CK, Taylor LJ, Hagedorn CH, O'Brien AD, Neish AS, Madara JL. (2001). Salmonella typhimurium translocates flagellin across intestinal epithelia, inducing a proinflammatory response. J Clin Invest, 107(1):99-109.

Sitaraman S, Gewirtz A, Williams I, L Wu, Madara JL. (2001). Adenosine produces polarized secretion of interleukin-6 in intestinal epithelial cells:bidirectional epithelial/neutrophil paracrine regulation in a model crypt abcess. J. Clin. Invest., 107:861-869.

Merlin D, Si-Tahar M, Sitaraman S, Eastburn K, Williams I, Liu X, Hediger M, Madara JL. (2001). Colonic epithelial hPepT1 expression occurs in inflammatory bowel disease: transport of bacterial peptides influences expression of MHC Class I molecules. Gastroenterology, 120(7): 1666-1679.

Nusrat A, VonEichel-Streiber C, Madara JL, Verkade P, Parkos CA. (2001). Disruption of tight junction structure and function by C. difficile toxins. Infect. and Immun. 69:1329-1336.

Liu Y, Merlin D, Burst SL, Pochet M, Madara JL, Parkos CA. (2001). The role of CD47 in neutrophil transmigration. Increased rate of migration correlates with increased cell surface expression of CD47. J Biol Chem, 276(43):40156-40166.

Merlin D, Sitaraman S, Liu X, Eastburn K, Sun J, Kucharzik T, Lewis B, Madara JL. (2001). CD98-mediated links between amino acid transport and beta 1 integrin distribution in polarized columnar epithelia. J Biol Chem, 276(42):39282-39289.

Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL. (2001). Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol, 167(4):1882-1885.

Sitaraman SV, Merlin D, Wang L, Wong M, Gewirtz AT, Si-Tahar M, Madara JL. (2001). Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediated by reciprocal secretion of adenosine and IL-6. J Clin Invest, 107(7):861-9.

Gewirtz AT, Madara JL. (2001). Periscope, up! Monitoring microbes in the intestine. Nat Immunol, 2(4):288-90.

Reed KA, Hobert ME, Kolenda CE, Sands KA, Rathman M, O’Connor M, Lyons S, Gewirtz AT, Sansonetti PJ, Madara JL. (2002). The Salmonella typhimurium Flagellar Basal Body Protein FliE Is Required for Flagellin Production and to Induce a Proinflammatory Response in Epithelial Cells. J Biol Chem, 277(15):13346-13353.

Yue G, Merlin D, Selsted ME, Lencer WI, Madara JL, Eaton DC. (2002). Cryptdin 3 forms anion selective channes in cytoplasmic membranes of human embryonic kidney cells. Amer J Physiol, 282(5):G757-765.

Collier-Hyams LS, Zeng H, Sun J, Tomlinson AD, Bao ZQ, Chen H, Madara JL, Orth K, Neish AS. (2002). Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-kappaB pathway. J Immunol, 169(6):2846-2850.

Sitaraman SV, Wang L, Wong M, Bruewer M, Hobert M, Yun CH, Merlin D, Madara JL. (2002). The Adenosine 2b Receptor Is Recruited to the Plasma Membrane and Associates with E3KARP and Ezrin upon Agonist Stimulation. J Biol Chem, 277(36):33188-33195.

Gewirtz AT, Collier-Hyams LS, Young AN, Kucharzik T, Guilford WJ, Parkinson JF, Williams IR, Neish AS, Madara JL. (2002). Lipoxin a4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression and reduce the severity of dextran sodium sulfate-induced colitis. J Immunol 2002;168(10):5260-5267.

Yue G, Merlin D, Selsted ME, Lencer WI, Madara JL, Eaton DC. (2002). Cryptdin 3 forms anion selective channels in cytoplasmic membranes of human embryonic kidney cells. Am J Physiol Gastrointest Liver Physiol, 282(5):G757-765.

Reed KA, Hobert ME, Kolenda CE, Sands KA, Rathman M, O'Connor M, Lyons S, Gewirtz AT, Sansonetti PJ, Madara JL. (2002). The Salmonella typhimurium flagellar basal body protein FliE is required for flagellin production and to induce a proinflammatory response in epithelial cells. J Biol Chem, 277(15):13346-53.

Kucharzik t, Gewirtz AT, Merlin D, Madara JL, Williams IR. Lateral membrane LXA4 receptors mediate LXA4’s anti-inflamatory actions on intestinal epithelium. Am J of Physiol ­ Cell Physiology, 284(4):C888-96, 2003.

Hobert ME, Sands KA, Mrsny RJ, Madara JL. (2002). Cdc42 and Rac1 regulate late events in Salmonella typhimurium-induced interleukin-8 secretion from polarized epithelial cells. J of Biol Chem, 277(52):51025-32.