Functional in vitro studies on the role and regulation of interleukin-6 in human somatotroph pituitary adenomas

Abstract

Objective: Interleukin-6 (IL-6), a member of the gp130 cytokine family, is considered to be an important modulator of function and growth in endocrine anterior pituitary cells. In pituitary adenomas, where IL-6 is often produced by the tumour cells, it is thought to be involved in pituitary adenoma pathophysiology via autocrine/paracrine mechanisms. Methods: We have studied in primary cell cultures of human somatotroph adenomas whether IL-6 stimulates growth hormone secretion and whether intratumoral IL-6 is affected by various IL-6-regulating factors.Results: Interleukin-6 stimulated GH secretion in 10 out of 11 somatotroph adenoma cultures (1.4-to 6.5-fold above basal levels). In comparative studies the GH-stimulatory potency of IL-6 was identical, or even stronger, than that of GHRH. In eight out of 11 adenoma cell cultures, IL-6 production was observed. This suggests that GH production might be stimulated by IL-6 in an autocrine/paracrine manner in these tumours. Dexamethasone strongly inhibited basal IL-6 secretion in all IL-6-producing adenoma cell cultures, whereas the IL-6 inhibitory or stimulatory action of other factors (octreotide, transforming growth factor-b1, insulin-like growth factor-I, pituitary adenylate cyclase-activating peptide and oestradiol) were heterogeneous in the different adenomas. Only transforming growth factor-a consistently stimulated IL-6 secretion in all of the adenomas studied. Conclusions: Intratumoral IL-6, which is differently regulated by various factors, might contribute to excessive GH production in the majority of somatotroph adenomas.

The regulatory mechanism by which interleukin-6 stimulates GH-gene expression in rat GH3 cells

“…After incubating GH3 cells with IL-6 for 4 h, we observed that GH release was significantly enhanced by 10 2 -10 4 U/ml IL-6. In accordance with our findings, Mainardi et al (2002) and Thiele et al (2003) also demonstrated that IL-6 significantly stimulated GH release from the primary cultured human somatotrope pituitary adenomas and pig pituitary cells. The GH-stimulatory potency of IL-6 was identical to, or even stronger than that of GHRH in comparative studies performed by Thiele et al (2003).…”

“…In accordance with our findings, Mainardi et al (2002) and Thiele et al (2003) also demonstrated that IL-6 significantly stimulated GH release from the primary cultured human somatotrope pituitary adenomas and pig pituitary cells. The GH-stimulatory potency of IL-6 was identical to, or even stronger than that of GHRH in comparative studies performed by Thiele et al (2003). Reduced expression of the cytokine transducer gp130, which is required for IL-6 signal transduction, by stably transfecting gp130 antisense into GH3 cells, inhibited IL-6-induced GH secretion and cell growth (Castro et al 2003).…”

Regulation of Pituitary Function by Cytokines

“…IL-6 stimulates the release of ACTH from AtT-20 cells and enhances its release from rat hemipituitary glands. IL-6 also stimulates both ACTH secretion and proopiomelanocortin gene expression in corticotrophic adenoma cell cultures [55], and stimulates GH secretion in somatotrophinomas [56]. Furthermore, IL-6 stimulates the release of PRL, GH and LH from dispersed cell cultures of normal rat pituitary cells [reviewed in [57]] and GH release from rat hemipituitary glands [54].…”

The role of the tumour microenvironment in immunotherapy

“…In pituitary adenomas, constitutively produced intratumoural IL-6 contributes to the excessive hormone secretion in endocrine-active tumours via autocrine and paracrine stimulation of the IL-6 receptor (Thiele et al 2003). This results in tumour expansion by concomitantly stimulating tumour cell proliferation and tumour neovascularisation (Renner et al 2009).…”