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Expression of Interleukin-6 and Its Effects on Growth of HP75 Human Pituitary Tumor Cells

Endocrine Heart and Pituitary Group, Academic Unit of Endocrinology (S.A.B., K.E.K., T.H.J.), Academic Unit of Pathology (L.B.), Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, United Kingdom S10 2RX; Center for Diabetes and Endocrinology, Barnsley District General Hospital (T.H.J.), Barnsley, S75 2EP United Kingdom; and Department of Pathology, University of Otago (J.A.R.), Otago, New Zealand

Address all correspondence and requests for reprints to: Dr. T. H. Jones, Endocrine Heart and Pituitary Group, Academic Unit of Endocrinology, Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield, United Kingdom S10 2RX. E-mail: hugh.jones{at}bdgh-tr.trent.nhs.uk.

The role of IL-6 in the pathogenesis of pituitary adenomas is unclear, as tumor biology is difficult to study in primary culture. We have shown here that the human pituitary cell line HP75 synthesizes IL-6 mRNA and expresses and secretes IL-6 (6167 ± 56 pg/ml/72 h for 30,000 cells). IL-6 receptor (IL-6R) mRNA was identified by in situ hybridization and RT-PCR. Exogenous IL-6 in low dose (1 ng/ml) stimulated, whereas higher doses (100 ng/ml) inhibited, growth. This diverse effect occurs in other cell types as a result of receptor down-regulation. Cell growth was inhibited by IL-6-blocking antibody (76 ± 6.5% inhibition; P < 0.0001). This demonstrates that IL-6 is an important growth regulator in HP75 cells, having an autocrine growth stimulatory effect under basal conditions. IL-1 and dibutyryl cAMP stimulated and dexamethasone inhibited IL-6 secretion; however, bacterial lipopolysaccharide, forskolin, and cholera toxin had no effect. This implies that there is a defect in the control of IL-6 secretion. Soluble IL-6R was not detected, but soluble gp130 receptor was present in the conditioned medium. Stimulation of cleavage of soluble IL-6R from the membrane-bound IL-6R could not be induced by phorbol ester or dexamethasone. Whether IL-6 has a similar effect in human pituitary adenomas requires further investigation.

This work was supported by Yorkshire Cancer Research (to Y.C.R.) and the Barnsley District General Hospital Endocrinology Research Fund.

Abbreviations: d, Deoxy; dbcAMP, dibutyryl cAMP; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IL-6R, IL-6 receptor; ISH, in situ hybridization; LPS, lipopolysaccharide; PDBu, phorbol-12–13-dibutyrate; sIL-6R, soluble IL-6R.

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