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Advances in Inflammatory Bowel Diseases Hollywood FL, 2013

Pro-inflammatory cytokines alter tight junction self- assembly and barrier function through claudin heterotypic incompatibility. Christopher T. Capaldo, Ph.D. Emory University. Advances in Inflammatory Bowel Diseases Hollywood FL, 2013. DISCLOSURES. Nothing to disclose.

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Advances in Inflammatory Bowel Diseases Hollywood FL, 2013

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  1. Pro-inflammatory cytokines alter tight junction self-assembly and barrier function through claudin heterotypic incompatibility. Christopher T. Capaldo, Ph.D. Emory University Advances in Inflammatory Bowel Diseases Hollywood FL, 2013

  2. DISCLOSURES • Nothing to disclose

  3. Barrier defects are linked to IBD. • Epithelial Tight Junctions provide the paracellular barrier. • Barrier properties depend on transmembraneclaudins. • Pro-inflammatory cytokines, such as IFN-g and TNF-a, disrupt Tight Junctions and claudin function. • Tight Junctions are dynamic structures.(Sasaki PNAS, 2003. Shen J Cell Bio.2008) • Fluorescence Recovery After Photobleaching (FRAP) • Are these dynamics disrupted in the presence of pro inflammatory cytokines?

  4. IFN-g/TNF-a increase claudin-4 dynamics (48hrs) Fluorescence Recovery After Photobleaching (FRAP) • Increased recovery • Little or no planar TJ diffusion.

  5. IFN-g/TNF-a increases claudin-4 partitioning into the mobile Junction sub-pool. • Cytokine alter Mf/If partitioning. • Cytokines do not alter t1/2 of recovery. • Does this reflect a change in TJ structure?

  6. IFN-g/TNF-a treatment does not alter gross TJ structure. • Freeze fracture EM • control • IFN-g/TNF-a • Ohms*cm2 • IFN-g/TNF-a • n=6 • control • IFN-g • TNF-a • (200nm) If not TJ structure, then is TJ composition changed? • Susanne Krug, Fromm Lab

  7. Claudin-4 excludes claudin-2 from the TJ.

  8. Claudin-4 excludes claudin-2 from the TJ. • Claudin 2 and 4 are heterotypically incompatible across cells, but not within the same cell. • (Daugherty 2007, Piontek, 2011) • Is this responsible for cytokine-induced changes in mobility? • Does this play a role in cytokine –induced barrier loss?

  9. Claudin 4 rescues cytokine-induced changes in mobility and barrier function • * • **

  10. Summary and working model • IFN-g/TNF-a increase claudin 2 levels (1). • Claudin 2 competes with claudin 4 at the junction. • Resulting in increased mobile pool claudin 4 and lower barrier function over time. • IFN-g/TNF-a • Claudin 4 • Claudin 2 TJ Immobile stands TJ mobile pool Lateral pool • (1. Mankertz, 2009)

  11. Nusratlab • AsmaNusrat • Roland Hilgarth • Mattie Feasle • Mike Kwon • Attila Farkas • Jeremy Benedik • KovalLab • Parkos Lab • Shroyer Lab • Fromm Lab • Susanne Krug Funded by a CCFA Career Development Award

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