The role of the transcription factor CREB in immune function

Abstract

CREB is a transcription factor that regulates diverse cellular responses, including proliferation, survival, and differentiation. CREB is induced by a variety of growth factors and inflammatory signals and subsequently mediates the transcription of genes containing a cAMP-responsive element. Several immune-related genes possess this cAMP-responsive element, including IL-2, IL-6, IL-10, and TNF-α. In addition, phosphorylated CREB has been proposed to directly inhibit NF-κB activation by blocking the binding of CREB binding protein to the NF-κB complex, thereby limiting proinflammatory responses. CREB also induces an antiapoptotic survival signal in monocytes and macrophages. In T and B cells, CREB activation promotes proliferation and survival and differentially regulates Th1, Th2, and Th17 responses. Finally, CREB activation is required for the generation and maintenance of regulatory T cells. This review summarizes current advances involving CREB in immune function--a role that is continually being defined.

FIGURE 1

Proposed model of how CREB inhibits NF-κB activity. NF-κB activity is initiated by TLRs (and other proinflammatory signals) that trigger MyD88/IRAK-4/TRAF6 activation and subsequent phosphorylation and degradation of IκB, allowing the active RelA (p65)/p50 NF-κB complex to enter the nucleus. Optimal transcriptional activity of NF-κB for certain target genes requires interaction of the RelA subunit with CBP or p300. Phosphorylated CREB, which occurs via activation of PKA, PKC, and others as indicated, has been shown to bind to the same region as CBP/p300, and this has been proposed as a mechanism for CREB in the inhibition of NF-κB activity and signaling (15, 16).

FIGURE 2

CREB-induced IL-10 production is regulated by IFN-γ. TLR signaling results in the activation of NF-κB and MAPKs (ERK1/2 and p38), which induces production of proinflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and the anti-inflammatory cytokine IL-10 (29). MAPKs activate MSK1 and MSK2 to directly phosphorylate CREB and AP-1, which bind to the IL-10 promoter and initiate transcription (32). This same pathway also induces dual-specificity protein phosphatase 1, which feeds back to inhibit p38 (32). Dectin-1, which recognizes zymosan, and the HIV-1 Tat protein also induce IL-10 production by activating CREB, Sp1, and Ets-1 through calmodulin, CaMK-II, and MAPKs (37-40). Finally, IFN-γ inhibits IL-10 production by 1) interfering with the PI3K-AKT pathway, thereby releasing GSK-3β, which subsequently downregulates the activation and transcriptional activity of CREB and AP-1 proteins that induce IL-10 production; and 2) directly inhibiting MAPKs (45, 55).

FIGURE 3

CREB promotes TGFβ-mediated generation and maintenance of FoxP3 Tregs. The TSDR in the FoxP3 locus is found methylated in conventional T cells. A, The methylation prevents phosphorylated CREB, which is induced by TCR activation, from binding to this region. B, TGF-β induces demethylation of the TSDR. C, Demethylation of the TSDR allows phosphylated CREB to bind to the FoxP3 locus to promote FoxP3 expression and the development and stabilization of Tregs (62-64). Transcription of FoxP3 also involves the formation of a “c-Rel enhanceosome”, which contains c-Rel, p65, NFAT, and Smad3 in addition to CREB (65).