Glucocorticoid- and cAMP-inducible genes with potential therapeutic activity in COPD

Gene ProductPutative Function(s)
GILZGILZ is a glucocorticoid-inducible gene that inhibits the transcriptional activity of both NF-κB and AP-1. Glucocorticoid-induced GILZ expression may also be modestly enhanced by LABAs. It is reported that induction of this gene suppresses various indices of inflammation (Mittelstadt and Ashwell, 2001).
RGS2RGS2 is a GTPase-activating protein that switches off signaling from Gq-linked GPCRs. In airway smooth muscle, RGS2 is upregulated in a positive cooperative manner by glucocorticoid and LABA, and exerts a bronchoprotective effect; in epithelial and other cells. RGS2 expression may attenuate proinflammatory mediator release (Holden et al., 2011).
CD200Pulmonary alveolar macrophages have high constitutive expression of CD200R. Signaling through this receptor involves the interaction of CD200R-bearing cells with other cells (e.g., airway epithelia) that express the glucocorticoid-inducible, cognate agonist CD200, which can be enhanced by formoterol and roflumilast alone and in combination. Studies in mice have shown that the CD200/CD200R interaction blunts macrophage activation measured as proinflammatory cytokine generation. Acute exacerbations of COPD are triggered, primarily, by prolonged bouts of excessive inflammation in response to bacterial and viral infections. Pharmacological upregulation of CD200 on epithelial and other airway cells in COPD could attenuate inflammation and reduce exacerbation frequency (Snelgrove et al., 2008).
CRISPLD2Previously known to mediate several other functions, CRISPLD2 was recently found to encode as a novel, secreted, mammalian LPS-binding protein in both humans and mice. Enhancement of FP-induced CRISPLD2 expression could contribute to the reduction in exacerbations in COPD produced by infections with gram-negative bacteria by downregulating TLR4-mediated proinflammatory responses (Wang et al., 2009).
p57kip2p57kip2 encodes a cell cycle kinase inhibitor that is induced by glucocorticoids in airway epithelial and other structural cells by a mechanism that is enhanced by formoterol and roflumilast, alone and in combination. Expression of this gene in relevant cells could arrest mitogenesis and suppress airway remodeling, which is a characteristic feature of COPD. p57kip2 may also block proinflammatory responses through its ability to inhibit one of the core mitogen-activated protein kinases, c-jun-N-terminal kinase (Samuelsson et al., 1999; Chang et al., 2003).
  • AP-1, activator protein-1; GPCR, G protein-coupled receptor; LPS, lipopolysaccharide; NF-κB, nuclear factor-κB; TLR4, toll-like receptor 4.