In their MKP-1 promoter analysis, Kwak et al. [
43] demonstrated that the putative
cis elements that might regulate MKP-1 gene expression included two CRE (positions −163 and −118 bp from the transcription start site). CRE is activated by cAMP and numerous publications in the past decade have shown that stimuli that increase cAMP in airway cells increase MKP-1. As elevation of intracellular cAMP in ASM cells is the mechanism of action responsible for the bronchodilatory impact of β
2-adrenergic agonists on bronchospasm, this CREB-linked transcriptional pathway has important consequences towards understanding the molecular mechanisms responsible for commonly-used respiratory medicines. This unifying, cAMP-dependent, principle links a diverse range of molecules with MKP-1 induction, including: the bioactive sphingolipid found increased in asthmatic airways, sphingosine 1-phosphate (S1P) [
79‐
81]; the cell-permeable cAMP elevating agent dibutyrl cAMP [
79]; the adenylate cyclase activator forskolin [
79]; short (salbutamol) and long-acting β
2-agonists (LABAs: formoterol and salmeterol) [
82‐
84]; inhibitors of phosphodiesterase 4 (PDE4) (including cilomilast, rolipram, piclamilast and roflumilast N-oxide), in combination with formoterol [
85,
86]; and prostaglandin E
2 [
87]. Research has conclusively shown that these molecules all increase cAMP in airway cells and result in increased MKP-1 production. In some investigations, CREB phosphorylation was also shown [
79], and the cAMP-dependent protein kinase A (PKA) pathway was implicated through the use of non-specific pharmacological inhibitors, such as H-89 [
83], or more conclusively demonstrated via adenoviral expression of the PKA inhibitor, PKIα [
83]. In elegant studies, Kaur et al. [
82] have used CRE-reporter constructs in BEAS-2B cells to confirm activation of CRE-dependent transcription in response to cAMP-elevating agents, including β
2-agonists. This was then linked to upregulation of anti-inflammatory genes, including MKP-1, in A549 and BEAS-2B epithelial cells. BinMahfouz et al. [
88] used epithelial cell models with CRE transcriptional activation to test combined PDE3 and PDE4 inhibitors and showed superior efficacy than with either inhibitor alone. Taken together, these studies show that cAMP-elevating agents increase MKP-1.