Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis.
We have previously demonstrated that STAT3 hyperactivation via the interleukin 6 (IL-6) cytokine family receptor gp130 in gp130 (Y757F/Y757F) mice leads to numerous hematopoietic and lymphoid pathologies, including neutrophilia, thrombocytosis, splenomegaly, and lymphadenopathy. Because IL-6 and IL-11 both signal via a gp130 homodimer, we report here a genetic approach to dissect their individual roles in these pathologies. Neutrophilia and thrombocytosis were absent in gp130 (Y757F/Y757F) mice lacking either IL-6 (gp130 (Y757F/Y757F): IL-6 (-/-)) or the IL-11 receptor alpha subunit (gp130 (Y757F/Y757F): IL-11Ralpha1 (-/-)), and this was associated with a normalized bone marrow compartment. The elevated myelopoiesis and megakaryopoiesis in bone marrow of gp130 (Y757F/Y757F) mice was attributable to an increase by either IL-6 or IL-11 in the STAT3-driven impairment of transforming growth factor beta (TGF-beta) signaling, which is a suppressor of these lineages. In contrast, the absence of IL-6, but not IL-11 signaling, prevented the splenomegaly, abnormal lymphopoiesis, and STAT3 hyperactivation in lymphoid organs of gp130 (Y757F/Y757F) mice. Furthermore, hyperactivation of STAT3 in lymphoid organs was associated with increased expression of IL-6Ralpha, and IL-6Ralpha expression was reduced in gp130 (Y757F/Y757F): Stat3 (+/-) mice displaying normal levels of STAT3 activity. Collectively, these data genetically define distinct roles of IL-6 and IL-11 in driving pathologic hematopoietic and lymphoid responses mediated by STAT3 hyperactivation.
Jenkins
Brendan J
BJ
Ludwig Institute for Cancer Research, Victoria, Australia. brendan.jenkins@med.monash.edu.au
Roberts
Andrew W
AW
Greenhill
Claire J
CJ
Najdovska
Meri
M
Lundgren-May
Therese
T
Robb
Lorraine
L
Grail
Dianne
D
Ernst
Matthias
M
D000483:Alleles; D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D017370:Interleukin-11 / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008206:Lymphatic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D053702:Receptors, Interleukin-11 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013163:Splenomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013922:Thrombocytosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
C494200:Il6st protein, mouse; D017370:Interleukin-11; D015850:Interleukin-6; D053702:Receptors, Interleukin-11; D050796:STAT3 Transcription Factor; D053773:Transforming Growth Factor beta1; D050822:Cytokine Receptor gp130