Peripheral blood IRF1 expression as a marker for glucocorticoid sensitivity

Abstract

Despite of the common usage of glucocorticoids (GCs), a significant portion of asthma patients exhibit GC insensitivity. This could be mediated by diverse mechanisms, including genomics. Recent work has suggested that measuring changes in gene expression may provide more predictive information about GC insensitivity than baseline gene expression alone, and that expression changes in peripheral blood may be reflective of that in the airway. Through gene expression omnibus (GEO) analysis, we identified IRF1 whose expression is affected by GC treatment in airway smooth muscle (ASM) cells, normal human bronchial epithelial (NHBE) cells, and lymphoblastoid cell lines (LCLs). Significant IRF1 down-regulation post GC exposure was confirmed in two cultured airway epithelial cell lines and primary NHBE cells (p<0.05). We observed large inter-individual variation for GC induced IRF1 expression changes among primary NHBE cells tested. Significant down-regulation of IRF1 was also observed in six randomly selected LCLs (p<0.05) with variable degree of down-regulation among different samples. In peripheral blood mononuclear cells (PBMCs) obtained from healthy volunteers, variable down-regulation of IRF1 by GC was also shown. NFKB1, a gene whose expression is known to be down-regulated by GC and the degree of down-regulation reflective of GC response, was used as a control in our study. IRF1 shows more consistent down-regulation across tissue types when compared to NFKB1. Our results suggest GC induced IRF1 gene expression changes in peripheral blood could be used as a marker to reflect GC response in the airway.

DUSP1 Maintains IRF1 and Leads to Increased Expression of IRF1-dependent Genes

“…In this respect, roles for IRF1 and CXCL10 in innate immunity, anti-viral defenses, and in the development of Th1 immunity are suggested and may be promoted by DUSP1 (16,26,60). Conversely, enhanced IRF1 expression is linked and/or associated with reduced glucocorticoid sensitivity (18,19). This may reflect that IRF1-dependent responses are maintained in the presence of glucocorticoids and, therefore, appear resistant.…”

“…Thus, a loss of MAPK activity could contribute to the maintenance of IRF1 expression in the presence of glucocorticoids. This may play a role in glucocorticoid insensitivity, and indeed enhanced expression of IRF1 is implicated in reduced responsiveness to glucocorticoids (18,19).…”

Identification of biomarkers for ischemic cardiomyopathy based on microarray data analysis

“…Recently, Chapin et al [41] indicated that the expression level of IRF1 was changed in the peripheral blood, which can be used as a marker to reflect the glucocorticoid response. IRF1 plays a key role in response to pressure or volume overload, which is involved in the pathogenesis of ischemic heart diseases [42].…”

Glucocorticoid receptor isoform‐specific regulation of development, circadian rhythm, and inflammation in mice

“…significantly elevated in the GR-C3 knockin spleens. Many of these genes and associated signaling pathways are known to be repressed by glucocorticoids (18)(19)(20)(21). Therefore, the inability of GR-C3 to fully counteract the LPSmediated rise in their expression suggests that additional GR translational isoforms are required for effective inhibition and resolution of inflammation.…”