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

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.