Glucocorticoid-Induced Leucine Zipper is Protective in Th1-Mediated Models of Colitis

Inflammatory bowel diseases are relatively common diseases of the gastrointestinal tract. The relative therapeutic efficacy of glucocorti¬coids used in inflammatory bowel diseases resides in part in their capability to inhibit activity of nuclear factor KB (NF-KB), a transcription factor central to the inflammatory process, and the consequent pro¬duction of T-helper 1 (Th1)-type cytokines. Previous studies indicate that increased expression in trans¬genic mice of glucocorticoid-induced leucine zipper (GILZ), a gene rapidly induced by glucocorticoids, inhibits NF-KB and Th1 activity. Methods: We per¬formed experiments with the aim to test the suscep¬tibility of GILZ transgenic (GILZ-TG) mice to dini¬trobenzene sulfonic acid–induced colitis. Results: Consistent with a decreased Th1 response, GILZ-TG mice were less susceptible to colitis induction as com¬pared with wild-type littermates, while they were more susceptible to Th2-mediated colitis. The inhibi¬tion was comparable to that obtained with dexameth¬asone treatment. Moreover, diminished intestinal tis¬sue damage, associated with inhibition of NF-KB nuclear translocation, interferon-y, tumor necrosis factor-a, and interleukin-1 production in CD4+ T lym¬phocytes of the lamina propria, was evident in GILZ-TG as compared with wild-type mice. In addition, inhibi¬tion of colitis development was also evident when GILZ fusion protein was delivered in vivo in dinitrobenzene sulfonic acid–treated WT animals as well as in interleu¬kin-10 knockout mice. Conclusions: Together these results demonstrate that GILZ mimics the effects of glucocorticoids, suggesting a contribution of this pro¬tein to the anti-inflammatory activity of glucocorticoids in Th1-induced colitis.