Journal of Pathology J Pathol 2004; 202: 41–49. Published online 27 November 2003 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/path.1476 Original Paper Immunohistochemical analysis of the IL-6 family of cytokines and their receptors in benign, hyperplasic, and malignant human prostate Mar Royuela, 1 Monica Ricote, 1 Melanie S Parsons, 2 Ignacio Garc´ ıa-Tu˜ n´ on, 1 Ricardo Paniagua 1 and Maria P De Miguel 2 * 1 Department of Cell Biology and Genetics, University of Alcala, Madrid, Spain 2 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA *Correspondence to: Dr Maria P De Miguel, Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th Street, BLSB Room 706, Philadelphia, PA 19107, USA. E-mail: M DeMiguel@mail.jci.tju.edu Received: 18 November 2002 Revised: 23 May 2003 Accepted: 13 August 2003 Abstract Interleukin-6 (IL-6) and its receptor have been implicated in prostate cancer progression. Because other members of the IL-6 family such as leukaemia inhibitory factor (LIF) and oncostatin M (OSM) share gp130, the signal transduction subunit of their receptors, interpretation of the data without considering the expression of these cytokines and their specific receptor subunits could be misleading. The immunohistochemical pattern of the IL-6 family and their receptor subunits in normal prostate, benign prostatic hyperplasia (BPH), and prostatic carcinoma (PC) was investigated. In normal prostates, gp130 and OSMRα were detected exclusively in the stroma and LIFRβ was very scarce. While IL-6 was scarcely immunolocalized to the basal cells of the epithelium, OSM was detected in the stroma and LIF in both the epithelium and the stroma. This suggests an autocrine role for this family of cytokines in the stroma of normal prostates. In BPH, gp130 and OSMRα were detected both in the epithelium and in the stroma, whereas LIFRβ was localized only to the epithelium. IL-6 localized preferentially to the epithelium, OSM to the stroma, and LIF to both compartments. Therefore, in addition to the autocrine role in the stroma, IL-6 and OSM may play a paracrine role from the stroma to the epithelium in BPH. In PC, gp130 and OSMRα were detected both in the epithelium and in the stroma, increasing with rising Gleason grade, whereas LIFRβ was localized exclusively to the epithelium of low Gleason grade carcinomas. IL-6, LIF, and OSM localized in all cell types, with immunostaining increasing with Gleason grade. These data suggest an autocrine role for these cytokines in the epithelial cells of PC. The distinct pattern of expression of LIFRβ exclusively in low Gleason grade carcinomas makes LIFRβ a candidate for malignancy diagnosis. The role of OSM mainly in high Gleason grade carcinomas makes OSM a putative target for prostate cancer therapy. Copyright  2003 John Wiley & Sons, Ltd. Keywords: prostate cancer; benign prostatic hyperplasia; IL-6; LIF; OSM; gp130 Introduction Prostate cancer constitutes a major and escalating health problem. The risk for a man in western society of developing prostate cancer is 30%, with about 10% progressing to clinical disease, making it the most commonly diagnosed, life-threatening malignancy in men [1]. Unlike most other cancer types, carcinoma of the prostate does not always constitute a serious threat to the life of the individual and, in fact, some elderly men die with prostate cancer rather than of prostate cancer [2]. The challenge is to distinguish those men whose prostate cancer is likely to lie quiescent from those who harbour more potentially aggressive neoplasms that justify radical treatment [2]. In this regard, identification of stage-specific malignancy markers as well as putative therapeutic targets is the most challenging frontier in prostate cancer today. The interleukin-6 (IL-6) family of cytokines com- prises IL-6, leukaemia inhibitory factor (LIF), onco- statin M (OSM), ciliary neurotrophic factor, IL-11, cardiotrophin-1 [3], and neurotrophin 1 [4]. Among this family, IL-6, LIF, and OSM are the most widely expressed in different organs and are asso- ciated with cancer progression [3]. They are glyco- proteins produced mainly by lymphocytes, endothelial cells, fibroblasts [5], and testicular somatic cells [6], and are present in human serum [7]. They inhibit the growth of many tumour cell lines [8], yet stim- ulate the proliferation of fibroblasts [9] and spermato- gonia [10]. All members of the IL-6 family share the common signal transduction subunit of their receptors, named gp130 [3,11]. The interaction of the ligand with its receptor involves binding of the ligand to a specific receptor component and then heterodimerization with the gp130 molecule [3]. It has been demonstrated that Copyright  2003 John Wiley & Sons, Ltd.