Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty

Abstract

Frailty is an important geriatric syndrome that predicts disability and mortality. Substantial evidence suggests inflammation marked by elevated IL-6 levels as a key pathophysiologic factor that contributes to frailty. CXCL-10, a potent pro-inflammatory chemokine, has increased levels with age and is implicated in several inflammatory conditions. To better understand molecular mechanisms of inflammation activation in frailty, we evaluated monocytic expression of CXCL-10 and other inflammatory pathway genes by pathway-specific gene array analysis and quantitative RT-PCR. Frailty status was determined by the validated criteria. Sixteen pairs of community-dwelling frail and age-, race-, and sex-matched non-frail participants (mean age 83 years, range 72-94) completed the study. Here we report that frail participants had higher CXCL-10 expression levels than matched non-frail controls (1.05+/-0.88 versus 0.53+/-0.39, p=0.04). CXCL-10 expression correlated with IL-6 levels only in frail participants (Spearman correlation coefficient r=0.52, p=0.03). Furthermore, frailty-associated CXCL-10 upregulation was highly correlated with IL-6 elevation, both measured by frail-over-non-frail ratios (r=0.93, p<0.0001). These findings suggest upregulated monocytic expression of CXCL-10 as an important molecular mechanism that contributes to inflammation activation in frail older adults. Therapeutic implications include potential development of CXCL-10-based interventional strategies for the prevention and treatment of frailty in older adults.

Fig. 1

Representative quantitative real time RT-PCR experiments demonstrating differential expression of CXCL-10 by unstimulated CD14⁺ monocytes from frail and matched non-frail older adults (Panel A). Expression of GAPDH (a house-keeping gene) in these experiments is shown in Panel B as the control.

Fig. 2

Correlation between CXCL-10 upregulation and IL-6 elevation as measured by frail-over-non-frail ratios of monocytic CXCL-10 expression or serum IL-6 levels (calculated for individual frail and matched non-frail pairs. Spearman correlation analysis demonstrated significant correlation between CXCL-10 upregulation and IL-6 elevation in frailty (r = 0.93, p < 0.0001).

Fig. 3

Hypothetical CXCL-10-mediated Th1 inflammation activation model pathway to the syndrome of frailty in older adults. The hypothetical causal directionality between CXCL-10 upregulation and IL-6 elevation remains to be determined in future longitudinal and/or interventional studies.