Intrapituitary Expression and Regulation of the gp130 Cytokine Interleukin‐6 and Its Implication in Pituitary Physiology and Pathophysiology

Abstract

Interleukin (IL)-6, a member of the gp130 cytokine family, is sometimes designated as an "endocrine" cytokine because of its strong regulatory influence on hormone production. Systemically acting IL-6 derived from immune cells is a potent stimulator of the hypothalamus-pituitary-adrenal axis and therefore plays an important role in modulating immune-neuroendocrine interactions during inflammatory or infectious processes. However, IL-6 is also produced within the anterior pituitary by so-called folliculostellate (FS) cells and is also synthesized in and released by tumor cells in pituitary adenomas. Growth factors (e.g., transforming growth factor-beta), neuropeptides (e.g., pituitary adenylate cyclase-activating polypeptide), or hormones (e.g., glucocorticoids) regulate IL-6 production both in FS and pituitary tumor cells. Interestingly, components of the innate immune system, such as toll-like receptor 4 and nucleotide-binding oligomerization domains (NODs), are expressed in FS and pituitary tumor cells. Therefore, cell-wall components of bacteria (lipopolysaccharide, muramyl dipeptide, diamino pimelic acid) stimulate IL-6 production in normal and tumoral pituitary. The intrinsic IL-6 production by FS cells in normal anterior pituitary may participate in immune-neuroendocrine interactions during inflammatory processes. In pituitary adenomas, IL-6 stimulates hormone secretion, tumor cell proliferation, and the production of angiogenic factors, such as vascular endothelial growth factor-A, suggesting an important role of IL-6 in the pathophysiology and progression of pituitary adenomas.

The role of the tumour microenvironment in immunotherapy

“…This results in tumour expansion by concomitantly stimulating tumour cell proliferation and tumour neovascularisation (Renner et al 2009). In nude mice studies, it was found that cytokines binding to the shared gp130 subunit of the IL-6 receptor contributed to tumour progression (Graciarena et al 2004, Renner et al 2009). The authors have not identified which cytokines were responsible for the effect.…”

Folliculo-stellate Cells: Paracrine Communicators in the Anterior Pituitary

“…IL-6 is a strong stimulant of the HPA axis and its expression is stimulated by TGF , PACAP and glucocorticoids [95,96]. At present it is Rat pituitary [73] TtT/GF cells [19] Leptin (common, ObRa and long, ObRb forms)…”

Hypoxia-induced VEGF production ‘RSUMEs’ in pituitary adenomas

“…These enigmatic cells constitute the major group of nonhormonal pituitary cells comprising approximately 5-10% of the anterior pituitary cell mass. With their characteristic stellate shape and long cytoplasmic processes, they form an intra-pituitary cell network coupled by gap junctions capable of transmitting intercellular signals in the gland and are associated with increased cell proliferation and hormone secretion in pituitary adenomas (Gloddek et al 1999, Renner et al 2009. In this article, Shan et al (2012) show that folliculostellate TtT-GF cells express RSUME suggesting that folliculostellate cells are exquisitely equipped to rapidly respond to local changes in oxygen concentrations to elicit RSUME-dependent production P P VEGF VEGF Figure 1 Possible RSUME-HIF1a-VEGF pathway in pituitary adenomas.…”