Hematopoietic growth factors and glucocorticoids synergize to mimic the effects of IL-1 on granulocyte differentiation and IL-1 receptor induction on bone marrow cells in vivo.
The mechanisms by which interleukin-1 (IL-1) stimulates hematopoiesis are not clear. We have previously shown that in vivo administration of IL-1 indirectly increases IL-1 receptor (IL-1R) expression on both immature and mature bone marrow (BM) cells, partly due to IL-1-induced hematopoietic growth factor (HGF) production. Because IL-1 also stimulates the hypothalamic pituitary-adrenal axis resulting in the production of glucocorticoids (GC), we assessed whether in vivo treatment with HGF and glucocorticoids upregulates IL-1R. Administration of IL-1 to adrenalectomized mice reduces by 53% IL-specific binding on light density bone marrow (LDBM) cells compared to sham-operated mice. The administration of dexamethasone (dex) alone induced only a slight increase in IL-1R expression but synergized with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), IL-3 and IL-6 to upregulate IL-1R expression. Flow cytometry analysis using the RB6-8C5 antibody, which is differentially expressed on myeloid cells, indicated that combined G-CSF and dex treatment acts to promote increased numbers of differentiated myeloid progenitors in the bone marrow. Autoradiographic analysis confirmed that while G-CSF and dex increased IL-1R expression on all myeloid cells, it was particularly pronounced for myelocytes, promyelocytes and metamyelocytes. These results suggest that the ability of IL-1 to enhance granulocyte differentiation in vivo is partly due to its ability to induce a cascade of cytokines and steroids which in turn regulate IL-1 receptor expression.
Dubois
C M
CM
Laboratory of Immunoregulation, NCI-Frederick Cancer Research & Development Center, MD 21702-1201.
Neta
R
R
Keller
J R
JR
Jacobsen
S E
SE
Oppenheim
J J
JJ
Ruscetti
F
F
D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001853:Bone Marrow / Q000187:drug effects / Q000648:ultrastructure; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016298:Hematopoietic Cell Growth Factors / Q000378:metabolism / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D017472:Receptors, Interleukin-1 / Q000032:analysis*; D015854:Up-Regulation / Q000187:drug effects
D000305:Adrenal Cortex Hormones; D005938:Glucocorticoids; D016298:Hematopoietic Cell Growth Factors; D007375:Interleukin-1; D007377:Interleukin-3; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D016179:Granulocyte Colony-Stimulating Factor; D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor