Dexamethasone-induced and estradiol-induced CREB activation and annexin 1 expression in CCRF-CEM lymphoblastic cells: evidence for the involvement of cAMP and p38 MAPK

Aims: Annexin 1 (ANXA1), a member of the annexin family of calcium-binding and phospholipid-binding proteins, is a key mediator of the anti-inflammatory actions of steroid hormones. We have previously demonstrated that, in the human lymphoblastic CCRF-CEM cell line, both the synthetic glucocorticoid hormone, dexamethasone (Dex), and the estrogen hormone, 17beta-estradiol (E(2)beta), induce the synthesis of ANXA1, by a mechanism independent of the activation of their nuclear receptors. Recently, it was reported that the gene coding for ANXA1 contains a cAMP-responsive element (CRE). In this work, we investigated whether Dex and E(2)beta were able to induce the activation of CRE binding proteins (CREB) in the CCRF-CEM cells. Moreover, we studied the intracellular signalling pathways involved in CREB activation and ANXA1 synthesis in response to Dex and E(2)beta; namely, the role of cAMP and the p38 mitogen-activated protein kinase (MAPK). Results: The results show that Dex and E(2)beta were as effective as the cAMP analogue, dBcAMP, in inducing CREB activation. On the contrary, dBcAMP induced ANXA1 synthesis as effectively as these steroid hormones. Furthermore, the cAMP antagonist, Rp-8Br-cAMPS, and the specific p38 MAPK inhibitor, SB203580, effectively prevented both Dex-induced, E(2)beta-induced and dBcAMP-induced CREB activation and ANXA1 synthesis. Conclusions: Taken together, our results suggest that, in CCRF-CEM cells, Dex-induced and E(2)beta-induced ANXA1 expression requires the activation of the transcription factor CREB, which in turn seems to be mediated by cAMP and the p38 MAPK. These findings also suggest that, besides the nuclear steroid hormone receptors, other transcription factors, namely CREB, may play important roles in mediating the anti-inflammatory actions of glucocorticoids and oestrogen hormones.