Table I. Summary of the many different roles of CREB in immune function
Role of CREBCell TypeAssociated FactorsOverall Role in Immune FunctionReferences
Inhibition of NF-κB signalingMonocytes and endothelial cellsCREB interacts with the RelA (p65) component of NF-κB at the same region as CBP/p300Anti-inflammatory (may be protective or pathogenic depending on the context)15, 16
Antiapoptotic survival signalMacrophagesTLR4 triggers NF-κB/MAPKs and MSK1/2, which activate PAI-2 and Bfl-1/A1 to phosphorylate CREBPathogenic (mechanism for pathogens to evade host immune responses)18, 19
TNF-α–mediated survival signalMacrophagesM. tuberculosis-derived adenylate cylcase (Rv0386) phosphorylates CREBPathogenic (promotes survival of M. tuberculosis in macrophages)20
Induction of IL-10Macrophages and myeloid dendritic cellsMAPKs (ERK1/2 and p38) trigger MSK1/2 to activate CREBAnti-inflammatory (may be protective or pathogenic depending on the context)29–32
Induction of IL-10MacrophagesTLR2 activation by Candida albicans triggers IL-10 productionPathogenic (promotes survival of Tregs, leading to disseminated candidiasis)31
Induction of IL-10 by HIV-1 TatMacrophagesSp1, Ets-1, calmodulin, CaMK-II, and MAPKsUnknown, may be pathogenic (macrophages could act as cellular viral reservoirs)38–40
Promotes T cell activation and proliferation and Th cell activityT cellsPKA, PKC, Ras, ERK1/2, pp90 RSK and CD28 (via p38 and CaMK-IV)May be protective or pathogenic (depending on the Ag)52, 53, 56–59
Promotes IFN-γ productionT cellsIFN-γ promoter is hypomethylated in Th1 cells, allowing CREB bindingProtective (promotes Th1 responses that are protective in tuberculosis)54, 55
Induction of FoxP3, promoting Treg generation and maintenanceT cellsTSDR in the FoxP3 locus, which allows CREB to promote FoxP3 expressionAnti-inflammatory (may be pathogenic relating to infections and tumor immunosurveillance and protective relating to autoimmunity)61–65
Promotes B cell activation and proliferationB cellsERK1/2, E1K-1, PKCδ, pp90 RSKMay be protective or pathogenic (depending on the Ag)66, 67