Abstract
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 (E2beta), 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 acAMP-responsive element (CRE). In this work, we investigated whether Dex and E2beta 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 E2beta; namely, the role of cAMP and the p38 mitogen activated protein kinase (MAPK). The results show that Dex and E2beta 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-8-Br-cAMPS, and the specific p38 MAPK inhibitor,SB203580, effectively prevented both Dex-induced, E2beta-induced and dBcAMP-induced CREB activation and ANXA1 synthesis. Taken together, our results suggest that,in CCRF-CEM cells, Dex-induced and E2beta-inducedANXA1 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.
Highlights
Annexin 1 (ANXA1) is a member of the annexin family of calcium-binding and phospholipid-binding proteins,[1,2] which is constitutively expressed in many human cells, in polymorphonuclear leukocytes.[1,3] Recently, we observed that ANXA1 is constitutively expressed in a human lymphoblastic T cell line, the CCRF-CEM cell line.[4]
In an attempt to understand the mechanisms by which Dex and E2b induce the synthesis of ANXA1, we have investigated the ability of these two steroid hormones to activate CRE binding proteins (CREB) in the CCRF-CEM cells
SB203580 alone had no effect on either the basal activation of CREB, or the basal expression of ANXA1. We found that both Dex and E2b induce CREB activation, and that the cAMP analogue dBcAMP is as effective as Dex and E2b in activating this transcription factor and in inducing ANXA1 synthesis, in CCRF-CEM cells
Summary
Annexin 1 (ANXA1) ( known as lipocortin 1) is a member of the annexin family of calcium-binding and phospholipid-binding proteins,[1,2] which is constitutively expressed in many human cells, in polymorphonuclear leukocytes.[1,3] Recently, we observed that ANXA1 is constitutively expressed in a human lymphoblastic T cell line, the CCRF-CEM cell line.[4] its biological role is still incompletely characterised, ANXA1 is considered an endogenous anti-inflammatory effector that mediates at least some of the anti-inflammatory actions of the glucorticoid (GC) hormones; namely, the inhibition of phospholipase A2, with the consequent suppression of prostaglandin and leukotriene production,[1] the inhibition of superoxide generation,[5] the inhibition of the activation, transmigration and phagocytic ability of neutrophils.[3] Recently, ANXA1 has been shown to mediate the inhibitory effect of GCs on the expression of cyclooxygenase-2 (COX2),6Á 8 an enzyme required for prostaglandin production and involved in cell proliferation.[9,10]. Some of the anti-inflammatory effects attributed to 17b-estradiol (E2b), the most potent oestrogen hormone, are identical to those exerted by ANXA1, suggesting that this protein may mediate the anti-inflammatory actions of E2b.11,12.
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