Transforming growth factor-beta 1 is required for secretion of IgG of all subclasses by LPS-activated murine B cells in vitro.

Abstract

Addition of transforming growth factor-beta 1 (TGF-beta 1) to in vitro cultures of murine B cells activated with bacterial LPS selectively stimulates IgG2b and IgA class switching and decreases cellular proliferation. To assess a possible role for endogenous TGF-beta in modulating the Ig isotypes produced by LPS-activated cells, we utilized a neutralizing anti-TGF-beta mAb to abrogate endogenous TGF-beta activity. Anti-TGF-beta antibody, over a range of relatively low cell densities, strikingly inhibited both IgG3 and IgG2b production in response to LPS, with little or no change in the concentrations of secreted IgM. This effect of anti-TGF-beta antibody was specific, since it did not occur with an isotype-matched control mAb and was completely reversed with exogenous TGF-beta 1. Optimal IgG3 secretion occurred at concentrations of TGF-beta that were approximately eightfold lower than that necessary for maximal synthesis of IgG2b. Neutralization of endogenous TGF-beta in LPS-activated cultures was associated with an approximately twofold increase in proliferation and viable cell yields, a modest decrease in the percentage of membrane (m)IgG2b+ cells, and a modest increase in the percentage of mIgG3+ cells. This latter finding indicated that TGF-beta was not required for IgG3 class switching, but for maturation of mIgG3+ cells into Ig secretors. Highly purified B cells, obtained by electronic cell sorting, released active TGF-beta in response to LPS and showed a similar marked reduction in LPS-mediated IgG3 and IgG2b secretion in the presence of anti-TGF-beta antibody. Abrogation of endogenous TGF-beta activity in LPS-activated cultures also resulted in a striking reduction in IFN-gamma-mediated IgG2a production, and a more modest decrease in the synthesis of IgG1 and IgE in the presence of IL-4. These data indicate that relatively low concentrations of TGF-beta are essential for stimulating optimal IgG secretion by LPS-activated B cells, in an Ig isotype-nonspecific manner, and may regulate these responses in an autocrine fashion.

TGF‐β1 reduces the differentiation of porcine IgA‐producing plasma cells by inducing IgM+ B cells apoptosis via Bax/Bcl2‐Caspase3 pathway

“…Moreover, it has been proposed that TGF‐β also limits the proliferation of human B cell precursors and ultimately their differentiation resulting in decreased IgM and IgD formation by inhibiting Ig mRNA synthesis and the switch from membrane‐bound form to secreted Ig form in human B cells 23,38 . However, some studies showed low‐dose TGF‐β1 promoted, whereas high‐dose inhibited IgG antibody secretion in murine B cells 21 . Interleukin‐21 (IL‐21) augments IgA production in PPs by promoting direct class switching and differentiation to IgA + B cells via the Jak–STAT pathway 10,12,39 .…”

“…20 In LPS-treated murine B cells, a low dose of TGF-β1 was promoted while a high dose inhibited IgA antibody secretion. 21 TGF-β1 and TGF-β3 suppressed B cell proliferation, differentiation of plasma cells and production of IgA in human peripheral blood B cells. 22,23 Accumulating evidence thus indicates that TGF-β1 affects IgA production, and this may differ between species, and it remains unclear how TGF-β1 regulates IgA antibody formation in porcine B cells.…”

“…The TGF‐β superfamily forms a large family of growth factors that regulate immune cell function 18 . TGF‐β1 is crucially involved in the production of IgA in mouse and human PPs by enhancing the transcription of GLα then subsequent CSR to IgA in mice 19–21 . In TGF‐β‐signaling‐deficient mice, serum IgA level decreased as well as IgA + cell numbers in the spleen and PPs 20 .…”

“…In TGF‐β‐signaling‐deficient mice, serum IgA level decreased as well as IgA + cell numbers in the spleen and PPs 20 . In LPS‐treated murine B cells, a low dose of TGF‐β1 was promoted while a high dose inhibited IgA antibody secretion 21 . TGF‐β1 and TGF‐β3 suppressed B cell proliferation, differentiation of plasma cells and production of IgA in human peripheral blood B cells 22,23 .…”

“…18 TGF-β1 is crucially involved in the production of IgA in mouse and human PPs by enhancing the transcription of GLα then subsequent CSR to IgA in mice. [19][20][21] In TGF-βsignalingdeficient mice, serum IgA level decreased as well as IgA + cell numbers in the spleen and PPs. 20 In LPS-treated murine B cells, a low dose of TGF-β1 was promoted while a high dose inhibited IgA antibody secretion.…”