External cytokines produced by cells of the innate immune system induce the differentiation of CD4+ T cells into helper T cell subsets with distinct functions and cytokine profiles. Apart from TH1 and TH2 cells a third subset of helper T cells has been described, which is characterized by increased expression of IL-17A, IL-17F, IL-21 and IL-22 (TH17 cells). TH17 cells are involved in the clearance of infectious agents and contribute to the expression of tissue damage in patients with autoimmune diseases including multiple sclerosis and systemic lupus erythematosus (SLE) (Korn et al., 2009). External cytokines like IL-6, IL-1β, IL-23 and TGF-β induce the generation of IL-17-producing cells, while IL-21 acts to perpetuate the production of IL-17 in T cells (Korn et al., 2007). Vice versa, IL-2 is able to suppress IL-17 production by orchestrating the balance between STAT5 and STAT3 phosphorylation and binding to the IL-17A promoter (Yang et al., 2011). The above-mentioned cytokines activate several transcription factors such as RORγt, RORα and aryl hydrocarbon receptor as lineage transcription factors as well as IRF-4, BAFF, and T-bet, which are involved in the control of IL-17 expression (Korn et al., 2009).
Cyclic AMP responsive element modulator (CREM) belongs to a family of transcription factors that also includes CREB and ATFs. They share high structural similarities characterized by a basic region and leucine zipper domains (Montminy, 1997) and bind to palindromic DNA sequences (TGACGTCA) as homo- or heterodimeric complexes (Sassone-Corsi, 1995). CREM proteins are encoded by a multiexonic gene that yields several isoforms through alternative splicing. The exon composition determines the functional propensities of the various isoforms as transcriptional activators or repressors.