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-β1, insulin-like growth factor-I, pituitary adenylate cyclase-activating peptide and oestradiol) were heterogeneous in the different adenomas. Only transforming growth factor-α 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.