Pre-pro-B cell growth-stimulating factor (PPBSF) upregulates IL-7Ralpha chain expression and enables pro-B cells to respond to monomeric IL-7.
Although pro-B cells are well represented in IL-7 knockout (KO) mice, they express abnormally low concentrations of the interleukin-7 receptor alpha-chain (IL-7Ralpha) and do not generate pre-B cells. Here, we demonstrate that pro-B cells from IL-7 KO mice can be induced to generate pre-B cells and immature B cells by exposure to recombinant IL-7 (rIL-7) in vivo but not in vitro. Experiments in recombinant activation gene-1 (RAG-1) KO mice indicate that the in vitro unresponsiveness of IL-7(-/-) pro-B cells to rIL-7 is unrelated to the absence of a functional pre-B cell receptor (pre-BCR). Rather, it appears to be due to the suboptimal expression of the IL-7Ralpha chain. Thus, IL-7(-/-) pro-B cells readily respond to rIL-7 in vitro if IL-7Ralpha chain expression is first upregulated by exposure to IL-7 in vivo or to IL-7(+/+) bone marrow (BM) stromal cells or conditioned medium (CM) therefrom in vitro. Similar results were obtained when pro-B cells from IL-7 KO mice were cultured on IL-7(-/-) BM stromal cells in the presence of rIL-7. This suggested that the recently described pre-pro-B cell growth-stimulating factor (PPBSF), a self-assembling hybrid cytokine comprising IL-7 and the stromal cell-derived hepatocyte growth factor beta-chain (HGFbeta), is required to stimulate pro-B cells from IL-7 KO mice. This inference was verified by demonstrating that purified PPBSF upregulates IL-7Ralpha chain expression on IL-7(-/-) pro-B cells in vitro and enables them to respond to rIL-7 in a stepwise manner. We, therefore, postulate that PPBSF is the operative form of IL-7 that normally induces IL-7Ralpha(lo) pre-pro-B cells to proliferate and differentiate into IL-7Ralpha(hi) pro-B cells, which then proliferate and differentiate into pre-B cells on stimulation with monomeric IL-7.
Department of Pathology, School of Medicine, University of Connecticut Health Center, Farmington, CT 06030-3105, USA.
Chiju
C
Wei
Laijun
L
Lai
Irving
I
Goldschneider
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology; D001853:Bone Marrow; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000737:chemistry / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019281:Dimerization; D005260:Female; D016654:Genes, RAG-1; D017228:Hepatocyte Growth Factor / Q000737:chemistry; D015851:Interleukin-7 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D017077:Culture Media, Conditioned; C515256:Cxcl12 protein, mouse; D015851:Interleukin-7; D021122:Protein Subunits; D020395:Receptors, Interleukin-7; D011994:Recombinant Proteins; C415350:interleukin-7 receptor, alpha chain; D017228:Hepatocyte Growth Factor