Short Communication Increased Expression of the Interleukin-11 Receptor and Evidence of STAT3 Activation in Prostate Carcinoma

Previous investigations have shown that interleukin-6, a member of the JAK-STAT activating family of cytokines, plays an important role in prostate carcinoma. Here we demonstrate the co-expression of another member of this cytokine family, interleukin-11 (IL-11), and components of its receptor (interleukin-11 receptor; IL-11R), ie, IL-11Ra (involved in ligand recognition), and gp130 (involved in signal transduction) in cultured normal and malignant prostate-derived epithelial cell lines. In the DU-145 prostate carcinoma cell line, rhIL-11 stimulates a transient and dose-dependent increase in the tyrosine 705phosphorylated, active form of STAT3 (STAT3 P-Tyr705), involved in the downstream signaling of IL-11R and other members of the gp130-dependent receptors. The ability of IL-11 to activate STAT3 in prostate-derived cells may be mechanistically important, given recent data suggesting that constitutively activated STAT3 may be associated with the malignant phenotype. In 51 human primary tissues derived from normal prostate, benign prostatic hyperplasia, and prostate carcinomas, IL-11Ra and gp130 were commonly expressed, with a statistically significant elevation in the expression of IL-11Ra in prostate carcinoma. Also, the tyrosine-phosphorylated, activated form of STAT3 was observed more prominently in the nuclei of cells residing in malignant glands compared to those in nonmalignant samples. Thus, the IL-11 receptor system is up-regulated in prostate carcinoma, and may be one part of a cytokine network that maintains STAT3 in its activated form in these tissues. (Am J Pathol 2001, 158:25–32) Prostate carcinoma is one of the leading causes of cancer deaths among men in the United States. As part of an effort to better understand the biology of normal prostate tissue and its neoplastic counterpart, we have been investigating the presence of cytokine and growth factor networks in these tissues, because these cell signaling systems play a key role in the cellular events that are important in malignancy, such as growth, cell survival, and motility. Here we report that the receptor for interleukin-11 (IL-11) is present in prostate-derived tissue, and is expressed to a greater degree in prostate carcinoma compared to nonmalignant prostate tissue. The IL-11 receptor (IL-11R) mediates the action of IL-11, a 19.1-kd pleiotropic cytokine that was initially cloned from a bone-marrow stromal cell line. Whereas the hematopoietic effects of IL-11, which include stimulation of megakaryocyte maturation and platelet production, and growth stimulation of CD34 hematopoietic progenitor cells, have been well studied, this cytokine has also been shown to mediate inhibition of adipogenesis, stimulation of osteoclasts, and cytoprotection of gut mucosa. The IL-11 receptor is a member of a family of cytokine receptors, sometimes referred to as the gp130-dependent family of receptors, which includes the receptors for IL-6, leukemia inhibitory factor, ciliary neurotrophic factor, oncostatin M, and cardiotrophin. The a subunit of the IL-11R, IL-11Ra, is required for high affinity binding of the ligand; on ligand binding, gp130, the subunit responsible for signal transduction, is recruited to the receptor complex. It is not known whether IL-11R-associated gp130 undergoes homodimerization, as it does in the case of the IL-6 receptor, or if an additional, as yet unidentified, subunit is involved. Among the signaling systems activated by IL-11R and other members of this