Glucocorticoid-Induced Leucine Zipper (GILZ) controls T lymphocytes differentiation

T. Frammartino, O. Bereshchenko, D. Sorcini, M. Biagioli, M. Cimino, M. Di Sante, A. Venanzi, S. Bruscoli, C. Riccardi. University of Perugia, Dept. of Clinical and Experimental Medicine, Section of Pharmacology 06122, Italy

GILZ (Glucocorticoid-Induced Leucine Zipper), a gene rapidly induced by dexamethasone, mediates some of the Glucocorticoid (GC)-induced effects and is involved in control of many cell functions including cell growth and differentiation. Most of these effects are due to GILZ interaction with NF-kB and MAPK pathway components. Using T-cell specific GILZ knock out (KO) mice (male, C57BL/6, 20-25 grams), we demonstrate GILZ is implicated in differentiation of T lymphocytes subsets.

GILZ KO T cells show Th1 unbalance of differentiation of Th1 and Th17 subpopulations. In particular, cells from GILZ KO mice showed an increased Th1 responses as evaluated by qPCR and ELISA analysis compared to WT control (n=5 per group). Moreover, consequent to this GILZ-mediated Th1 polarization we found an increased susceptibility to inflammatory process development in vivo. In fact, using a DNBS-induced colitis experimental model, we found an augmented disease induction in GILZ KO mice as compared to WT littermates (n=5 per group). Evaluation of clinical score, macroscopic and microscopic analysis on intestine indicated inflammatory response contributing to increased disease in GILZ KO mice. As a demonstration of a major susceptibility of KO mice to colitis we observed a higher weight loss in KO mice compared to WT mice (mean of weight loss is 5% in WT and 20% in KO, p < 0,05, Student’s t-test), different colon length (mean of length is 6,7 cm in WT and 5,9 cm in KO, p < 0,05) and different diarrhea score (1,6 in KO and 0,4 in WT, p < 0,05).

In conclusion, these results indicate that GILZ contributes to T lymphocytes differentiation and mediates the immuno-regulatory effect of GC.