IntroductionHodgkin disease (HD) is characterized by a disruption of the lymph node architecture with low numbers of Hodgkin and Reed-Sternberg (H-RS) cells surrounded by an abundance of reactive nonmalignant cells. 1,2 This histologic pattern of HD may be due to the production and release of cytokines from H-RS cells that are involved in the growth of the lymphoma cells and the interactions with bystander cells. [3][4][5] Recently it has been shown that HD cell lines and primary H-RS cells express interleukin-6 (IL-6) and the ␣-chain of the IL-6 receptor (IL-6R; gp80). 3,4,6 IL-6 is synthesized by a variety of cells on stimulation and acts on a wide range of different target cells to regulate cell growth, differentiation, or gene expression. 7,8 IL-6 may act as an autocrine or paracrine growth factor for multiple myeloma, Epstein Barr virus (EBV)-immortalized B cells, and perhaps for H-RS cells, although this has not been proven yet for HD. 3,7,9-13 IL-6 exerts its action via a cell surface receptor complex consisting of at least 2 subunits: the IL-6R gp80 and the signal transducer gp130. 8,14 It has been shown that gp80 is not expressed on normal resting B cells and most Burkitt lymphoma (BL) cell lines 15 ; gp130 is shared by a number of cytokines as a signal transducing receptor component that does not bind IL-6 by itself. 7,8,16 The binding of IL-6 to gp80 leads to an association and dimerization of gp130, followed by the rapid activation of tyrosine kinases of the Janus family (Jak) and a subsequent activation of transcription factors of the signal transducers and activators of transcription (STAT) family. [17][18][19] STAT proteins are latent cytoplasmic transcription factors that become activated by tyrosine phosphorylation in response to a number of cytokines. STATs become phosphorylated and translocate as homodimers and heterodimers to the nucleus, where they bind to defined DNA elements within the promoter region of target genes and activate their transcription. [19][20][21] The activation by IL-6 is mainly associated with the tyrosine phosphorylation of STAT3. 19,22 Besides this extracellular mechanism of STAT activation by cytokines evidence also suggests that intracellular events may influence the activation state of STAT proteins and render them independent of extracellular stimuli. Constitutive STAT activation has been reported by several authors for acute leukemias, multiple myeloma, or breast cancer. 13,[23][24][25][26][27][28][29] To further explore the putative role of IL-6 in HD, the expression of gp130 and the influence on the activation of STAT proteins in HD cell lines was analyzed. Neutralizing monoclonal antibodies against IL-6, gp80, gp130, or both receptor subunits did not affect the proliferation of the HD cells or the constitutive activation of STAT molecules. However, the tyrosine kinase inhibitor AG490 inhibited both the constitutive activation of STAT3 and the growth of Hodgkin cell lines in vitro.
Materials and methods
Cell linesThe HD cell lines L1236, L428, L540, HDLM2, Dev, a...