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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.