TGF-beta down-regulates stromal IL-7 secretion and inhibits proliferation of human B cell precursors.
Development of lymphoid progenitors in vivo requires interaction with a bone marrow stromal microenvironment containing multiple cytokines involved in the development of nonlymphoid hemopoietic lineages. We tested the effect of one such cytokine, TGF-beta, on the proliferation of early human clonogenic lymphoid progenitors using a stroma-dependent in vitro culture system. TGF-beta caused a dose-dependent inhibition of lymphoid progenitor colonies that was reversible at low TGF-beta doses by addition of exogenous IL-7 to the cultures. IL-7 was unable to reverse the inhibitory effect of higher TGF-beta concentrations or inhibition caused by IL-1alpha, IL-4, or TNF-alpha. Stromal IL-7 mRNA expression and protein secretion were markedly down-regulated by TGF-beta, suggesting that inhibition of stromal IL-7 secretion partially accounts for the inhibitory effect of TGF-beta on lymphopoiesis in this culture system. It is likely that higher TGF-beta concentrations do not inhibit lymphopoiesis by down-regulating IL-7 receptor expression, since this cytokine did not reduce IL-7R alpha or gamma c mRNA levels in normal B cell precursors. Since direct stromal contact is required for in vitro lymphopoiesis, the potential regulation of the IL-7 pathway by cell adhesion was examined. Adhesion of human B cell precursors to stroma did not alter stromal IL-7 expression or expression of IL-7R alpha or gamma c-chains by B cell precursors. These results indicate that TGF-beta is a significant negative regulator of stroma-dependent proliferation of early human lymphoid progenitors and acts in part by down-regulating stromal IL-7 secretion.
Tang
J
J
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, NY 14642, USA.
Nuccie
B L
BL
Ritterman
I
I
Liesveld
J L
JL
Abboud
C N
CN
Ryan
D H
DH
D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism*; D017154:Stromal Cells / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D015851:Interleukin-7; D016212:Transforming Growth Factor beta