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 abundant reactive nonmalignant cells. It has been suggested that cytokines such as interleukin-6 (IL-6) are involved in the pathogenesis of the disease. The expression of the IL-6 receptor (IL-6R) complex and its link to the activation of signal transducers and activators of transcription (STAT) molecules in HD cell lines was investigated. Gel retardation and Western blot analyses revealed a high level of constitutively activated STAT3 in 5 of 7 HD cell lines, which could not be detected in Burkitt lymphoma cell lines. Different levels of IL-6R protein were measured in various HD cell lines: L428 and Dev cells were characterized by very low levels of gp80 and gp130, on KMH2 cells only gp130 but no gp80 was detected, whereas L540, L591, HDLM2, and L1236 were positive for both gp80 and gp130, suggesting a possible autocrine stimulation of STAT3. However, a further increase in STAT3 activation on IL-6 or IL-6/soluble IL-6R stimulation was not observed. Neutralizing monoclonal antibodies against IL-6, gp80, gp130, or both receptor subunits did not affect the proliferation or the constitutive activation of STAT molecules 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 regulation in Hodgkin cell lines. (Blood. 2001;98:762-770)
Kube
D
D
Klinik für Innere Medizin I, Zentrum für Molekulare Medizin der Universität Köln, Germany. dieter.kube@uni-tuebingen.de
Holtick
U
U
Vockerodt
M
M
Ahmadi
T
T
Haier
B
B
Behrmann
I
I
Heinrich
P C
PC
Diehl
V
V
Tesch
H
H
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006689:Hodgkin Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology; D007938:Leukemia / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019947:Receptors, Interleukin-6 / Q000276:immunology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; C113250:interleukin-6 receptor alpha; D050822:Cytokine Receptor gp130; D011505:Protein-Tyrosine Kinases