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Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis.
- Source :
-
Blood [Blood] 2007 Mar 15; Vol. 109 (6), pp. 2380-8. Date of Electronic Publication: 2006 Nov 02. - Publication Year :
- 2007
-
Abstract
- 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.
- Subjects :
- Alleles
Animals
Cytokine Receptor gp130 genetics
Cytokine Receptor gp130 metabolism
Gene Expression Regulation
Interleukin-11 pharmacology
Interleukin-6 deficiency
Interleukin-6 genetics
Lymphatic Diseases genetics
Lymphatic Diseases metabolism
Lymphatic Diseases pathology
Mice
Mice, Transgenic
Receptors, Interleukin-11 metabolism
Signal Transduction
Splenomegaly genetics
Splenomegaly metabolism
Splenomegaly pathology
Thrombocytosis genetics
Thrombocytosis metabolism
Thrombocytosis pathology
Transforming Growth Factor beta1 metabolism
Hematopoiesis
Interleukin-11 metabolism
Interleukin-6 metabolism
Lymphocytes cytology
Lymphocytes metabolism
STAT3 Transcription Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 109
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 17082315
- Full Text :
- https://doi.org/10.1182/blood-2006-08-040352