Elevated Serum Interferon-γ-Inducible Chemokine-10/CXC Chemokine Ligand-10 in Autoimmune Primary Adrenal Insufficiency andin VitroExpression in Human Adrenal Cells Primary Cultures after Stimulation with Proinflammatory Cytokines

Abstract

Chemokines are a large family of cytokines involved in the pathogenesis of inflammatory and autoimmune diseases. Among CXC chemokines, CXC chemokine ligand 10 (CXCL10) has been identified to play an important role in several endocrinological autoimmune diseases, such as Hashimoto's thyroiditis, Graves' disease, and type 1 diabetes mellitus. Although the mechanisms leading to glandular autoimmune process may be at least in part shared by different endocrine organs, the role of CXCL10 in autoimmune adrenal insufficiency is unknown. The aim of this study was to evaluate the role of CXCL10 in Addison's disease (AD). Serum CXCL10 levels were assayed in 64 patients with clinically evident autoimmune AD, 20 patients with autoimmune subclinical AD, nine patients with nonautoimmune AD, and 48 healthy volunteers. Clinically evident and subclinical AD, but not nonautoimmune AD patients, showed a significant increase in serum CXCL10 levels compared with healthy subjects: 119.9 pg/ml (range, 39.8-427.6) and 124.0 pg/ml (range, 37.0-384.7) vs. 75.6 pg/ml (range, 22.4-164.0; P < 0.001 for both groups). Comparable serum CXCL10 levels were found between patients with an isolated form of AD and patients with other autoimmune conditions associated with AD, suggesting a specific influence of the adrenal autoimmune process in determining elevated CXCL10 concentrations in such patients. No relationship was found between serum CXCL10 levels and anti-21-hydroxylase or adrenal cortex autoantibody titers or between CXCL10 levels and duration of disease. The role of CXCL10 in the adrenal gland was also evaluated in vitro in human zona fasciculata cells (hZFC). CXCL10, although not basally detected in cultured hZFC, was strongly induced by interferon-gamma and synergistically increased by TNF-alpha addition. Hydrocortisone or ACTH alone had no effect on CXCL10 secretion in hZFC, but they both significantly inhibited cytokine-induced CXCL10 secretion. Taken together, these data suggest a potential role of hZFC, through the production of CXCL10, in regulating the recruitment of specific subsets of activated lymphocytes in autoimmune AD.

Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes

“…In particular, the synergy between the two cytokines is essential in potentiating inflammatory and Th1 immune responses promoted by IFNg. To date, previous studies reported that CXCL10 secretion is triggered only by IFNg in different resident cell types (Rotondi et al 2005, Antonelli et al 2006d, while in microvascular endothelium TNFa has been reported to upregulate cytokines other than CXCL10 (Sana et al 2005).…”

Role of Chemokines in Endocrine Autoimmune Diseases

“…The effect of corticosteroids on cytokine-induced CXCL10 secretions was studied in primary cell cultures of human zona fasciculata cells (hZFC) from normal adrenal glands (211). CXCL10 was undetectable basally, whereas its secretion was significantly induced in hZFC by stimulation with IFN-␥ or IFN-␥ plus TNF-␣ (Fig.…”

Autoimmunity to Steroid-Producing Cells

“…The absence of a gender-related effect in AAD, either isolated or occurring within APS-2, suggested that autoimmune adrenalitis by itself was responsible for the high circulating levels of CXCL10. In the same study (Rotondi et al, 2005), it was also shown that release of CXCL10 by primary cell cultures of human zona fasciculata cells (hZFC) was undetectable basally, but significantly induced by stimulation with IFN- or IFN- plus TNF-, while stimulation of hZFC with TNF- alone was not able to induce chemokine secretion. Interestingly, increasing concentrations of hydrocortisone progressively and significantly inhibited IFN--induced and IFN--plus TNF--induced CXCL10 secretion (Rotondi et al, 2005).…”

“…In the same study (Rotondi et al, 2005), it was also shown that release of CXCL10 by primary cell cultures of human zona fasciculata cells (hZFC) was undetectable basally, but significantly induced by stimulation with IFN- or IFN- plus TNF-, while stimulation of hZFC with TNF- alone was not able to induce chemokine secretion. Interestingly, increasing concentrations of hydrocortisone progressively and significantly inhibited IFN--induced and IFN--plus TNF--induced CXCL10 secretion (Rotondi et al, 2005). The inhibitory effect of glucocorticoids on chemokine production is in line with their antiinflammatory and immunosuppressive actions.…”

“…The existence of an important IFN--mediated pathogenetic loop has been proposed for endocrine autoimmunity, as release of CXCR3-binding chemokines is stimulated by IFN- and, in turn, these chemokines recruit Th-1 cells that produce IFN- (Rotondi et al, 2007). In one report concerning the role of serum CXCL10 in AAD, serum levels of CXCL10 were significantly increased in patients with either clinically evident or subclinical adrenal insufficiency, as compared to healthy control subjects (Rotondi et al, 2005). The absence of a gender-related effect in AAD, either isolated or occurring within APS-2, suggested that autoimmune adrenalitis by itself was responsible for the high circulating levels of CXCL10.…”