Higher IL-6 and IL6:IGF Ratio in Patients with Barth Syndrome

Abstract

BackgroundBarth Syndrome (BTHS) is a serious X-linked genetic disorder associated with mutations in the tafazzin gene (TAZ, also called G4.5). The multi-system disorder is primarily characterized by the following pathologies: cardiac and skeletal myopathies, neutropenia, growth delay, and exercise intolerance. Although growth anomalies have been widely reported in BTHS, there is a paucity of research on the role of inflammation and the potential link to alterations in growth factors levels in BTHS patients.MethodsPlasma from 36 subjects, 22 patients with Barth Syndrome (0.5 - 24 yrs) and 14 healthy control males (8 - 21 yrs) was analyzed for two growth factors: IGF-1 (bound and free) and Growth Hormone (GH); and two inflammatory cytokines IL-6 and TNF-α using high-sensitivity enzyme-linked immunosorbent assays.ResultsThe average IL-6 and IL6:IGF ratio levels were significantly higher in the BTHS (p = 0.046 and 0.02 respectively). As for GH, there was a significant group by age interaction (p = 0.01), such that GH was lower for BTHS patients under the age of 14.4 years and higher than controls after age 14.4 years. TNF-α levels were not significantly different, however, the TNF-α:GH was lower in BTHS patients than controls (p = 0.01).ConclusionsComparison of two anabolic growth mediators, IGF and GH, and two catabolic cytokines, IL-6 and TNF-α, in BTHS patients and healthy age-matched controls demonstrated a potential imbalance in inflammatory cytokines and anabolic growth factors. Higher rates of IL-6 (all ages) and lower GH levels were observed in BTHS patients (under age 14.5) compared to controls. These findings may implicate inflammatory processes in the catabolic nature of Barth Syndrome pathology as well as provide a link to mitochondrial function. Furthermore, interactions between growth factors, testosterone and inflammatory mediators may explain some of the variability in cardiac and skeletal myopathies seen in Barth Syndrome.

Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4

“…Saturation of CL leads to defective mitochondrial bioenergetics and explains why BTHS patients have cardiac and skeletal myopathy. It is not known whether changes in CL saturation are also linked to the chronic inflammation and neutropenia in BTHS [8–10].…”

Barth syndrome

“…A study of 22 BTHS patients aged between 4 months and 24 years reported subnormal levels of growth hormone (GH) below 14.4 years, but levels higher than controls above this age, most marked at 19–20 years [74]. Insulin-like growth factor-1 (IGF-I) deficiency has been reported; as expected for constitutional growth delay, the patient had normal GH release and no other sign of pituitary dysfunction.…”

Tafazzin (TAZ) promotes the tumorigenicity of cervical cancer cells and inhibits apoptosis

“…In recent years, overexpression of TAZ has been observed in several tumors, including colon cancer[ 16 ], rectal cancer[ 17 ] and thyroid neoplasms[ 18 ]. Additionally, abnormal TAZ expression combined with higher IL-6 expression was found to promote inflammatory responses, which are commonly considered a predisposition factor for cancer progression[ 19 ]. However, the function of TAZ in cervical carcinogenesis is still not fully understood.…”