Interleukin 2 and systemic lupus erythematosus: beyond the transcriptional regulatory net abnormalities

IL-2 plays a key role in setting the balance between immunity and tolerance. This cytokine has a dual role as the regulator of the two main phases of the immune response (proliferative and suppressive). Likewise, activation induced cell death and the induction and maintenance of regulatory T cells are the tolerance mechanisms regulated by IL-2, which convey the link between IL-2 abnormalities and the development of autoimmune disorders, such as systemic lupus erythematosus (SLE). Particularly, in SLE murine models and in humans, deficiency in IL-2 synthesis and activity has been proven. Diverse signaling pathways abnormalities (TCR, NF-kappaBeta, NF-AT) have been involved in the IL-2 transcriptional dysregulation displayed by T cells from SLE patients, and its functional relevance as part of the physiopathogenic scheme has been shown. Aberrant expression and activity of multiple IL-2 transcriptional factors, such as c-fos, and predominantly, CREM and CREB have been involved in this immune dysregulation. Diverse alterations in signaling kinases and phosphatases (PKA, PP2A, CAMKIV) and the modulation by epigenetic mechanisms have been related to the altered CREM/pCREB index. The synergic effect of multiple abnormalities in the transcriptional factors previously mentioned has been shown to be of functional relevance in lupus.