STAT3 is constitutively activated in Hodgkin cell lines

Hodgkin disease (HD) represents a malignant lymphoma in which the putative malignant Hodgkin and Reed-Sternberg cells are rare and surrounded by abund ant reactive nonmalignant cells. It has been suggested that cytokines such as interleukin-6 (IL-6) are involved in the pathogenesis of the disease. Th e expression of the IL-6 receptor (IL-6R) complex and its link to the activ ation of signal transducers and activators of transcription (STAT) molecule s in HD cell lines was investigated. Gel retardation and Western blot analy ses revealed a high level of constitutively activated STAT3 in 5 of 7 HD ce ll lines, which could not be detected in Burkitt lymphoma cell lines. Diffe rent levels of IL-6R protein were measured in various HD cell lines: L428 a nd Dev cells were characterized by very low levels of gp80 and gp130, on KM H2 cells only gp130 but no gp80 was detected, whereas L540, L591, HDLM2, an d L1236 were positive for both gp80 and gp130, suggesting a possible autocr ine stimulation of STAT3. However, a further increase in STAT3 activation o n IL-6 or IL-6/soluble IL-6R stimulation was not observed. Neutralizing mon oclonal antibodies against IL-6, gp80, gp130, or both receptor subunits did not affect the proliferation or the constitutive activation of STAT molecu les in HD cell lines. However, the tyrosine kinase Inhibitor AG490 blocked the constitutive activation of STAT3 and inhibited spontaneous growth of HD tumor cells. The evidence suggests abnormal STAT signaling and growth regu lation in Hodgkin cell lines. (C) 2001 by The American Society of Hematolog y.