Distinct requirements for Stat4 and Stat6 in hematopoietic progenitor cell responses to growth factors and chemokines.
Hematopoietic progenitor cell (HPC) homeostasis is critical in maintaining innate immunity and healing processes. Recently, we demonstrated that Th1 cells regulate HPC homeostasis, partly based on altered homeostasis in Stat4- and Stat6-deficient mice. To explore changes in HPC responsiveness in altered T helper cell environments, we directly examined growth factor-stimulated colony formation and chemokine-induced myelosuppression of HPC in Stat4- and Stat6-deficient bone marrow cells. Stat6-deficient cells have increased responses to the synergy between granulocyte-macrophage colony-stimulating factor (GM-CSF) and steel factor (SLF), compared to wild-type and Stat4-deficient cells. Increased responses are eliminated by in vivo depletion of CD4 cells. Whereas Stat6-deficient bone marrow cells respond to chemokine-mediated myelosuppression, Stat4-deficient bone marrow cells are refractory to the suppressive effects of chemokines. Thus, T helper cell development affects HPC homeostasis through several mechanisms, including the sensitivity to growth factor stimulation and chemokine suppression of HPC colony formation. Since Stat4 and Stat6 regulate opposing programs of T helper differentiation, there are distinct requirements for Stat4 and Stat6 in regulation of growth factor and chemokine responses of HPC.
Kaplan
Mark H
MH
Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA. mkaplan2@iupui.edu
Chang
Hua-Chen
HC
Cooper
Scott
S
Lee
Younghee
Y
Broxmeyer
Hal E
HE
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D018925:Chemokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D012260:Ribonucleases / Q000378:metabolism; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D019089:Stem Cell Factor / Q000378:metabolism; D013234:Stem Cells; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D015534:Trans-Activators / Q000502:physiology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D018925:Chemokines; D004268:DNA-Binding Proteins; D006133:Growth Substances; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D019089:Stem Cell Factor; D015534:Trans-Activators; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D012260:Ribonucleases