SLE patients also display increased expression and enzymatic activity of protein phosphatase (PP)-2A, which specifically de-phosphorylates specificity protein (SP)-1 at serine residue 59. De-phosphorylated SP-1 binds to and trans-activates CREM P1, contributing to the enhanced basal CREMα expression in T cells from SLE patients [24,29,30]. Given that SP-1 expression is significantly enhanced in response to estrogen receptor engagement, this mechanism may contribute to the female predominance in SLE [31]. In contrast to P1, the intronic CREM promoter P2 is under the tight transcriptional control of activating protein (AP)-1 in response to T cell activation mediated through stimulation with anti-CD3/anti-CD28 or phorbol myristate acetate (PMA)/ionomycine [32]. In T cells from healthy individuals, T cell activation increases AP-1 recruitment to P2 with subsequent promoter activation and enforced CREMα transcription. Because AP-1/c-fos expression is decreased in SLE T cells (largely due to transcriptional repression by CREMα itself [33]), these cells fail to upregulate CREMα expression following T cell activation. Thus, the AP-1:CREMα axis is an important autoregulatory loop that eventually limits a further increase of CREMα expression in SLE T cells. This may be beneficial in light of the multiple deleterious effects CREMα exerts on cytokine expression in SLE pathogenesis.
