坂本 明美

Bcl6-deficient (Bcl6(-/-)) mice displayed Th2 type inflammation, which caused by abnormality of non-lymphoid cells. However, initiators for the Th2 type inflammation were not clear. In order to elucidate the initiators, we investigated property and function of mast cells derived from Bcl6(-/-) mice. Mast cells were developed from bone marrow cells cultured with IL-3 (BMMCs). Although the development of BMMCs from Bcl6(-/-) mice was similar to that from wild-type mice, proliferation of Bcl6(-/-) BMMCs stimulated with IL-3 was slightly lower than that of wild-type BMMCs. When these BMMCs were stimulated by Fc epsilon RI/IgE cross-linking, Bcl6(-/-) BMMCs produced Th2 cytokines more than wild-type BMMCs did. Thus, Bcl6(-/-) mast cells are one of the initiators for Th2 type inflammation in Bcl6(-/-) mice, and Bcl6 may be a molecular target for Th2 type allergic diseases. (c) 2005 Elsevier Ltd. All rights reserved.

The role of transforming growth factor (TGF)-beta and its signal in atherogenesis is not fully understood. Here, we examined mice lacking Smad3, a major downstream mediator of TGF-beta, to clarify the precise role of Smad3-dependent signaling in vascular response to injury. Femoral arteries were injured in wild-type and Smad3-null ( null) male mice on C57Bl/6 background. Histopathological evaluation of the arteries 1 to 3 weeks after the injury revealed significant enhancement of neointimal hyperplasia in null compared with wild-type mice. Transplantation of null bone marrow to wild-type mice did not enhance neointimal thickening, suggesting that vascular cells in situ play a major role in the response. Null intima contained more proliferating smooth muscle cells (SMC) with less amount of collagen compared with wild-type intima. TGF-beta caused significant inhibition of cellular proliferation in wild-type aortic SMC, whereas the growth of null SMC was only weakly inhibited by TGF-beta in vitro, indicating a crucial role of Smad3 in the growth inhibitory function. On the other hand, Smad3-deficiency did not attenuate chemotaxis of SMC toward TGF-beta. TGF-beta increased transcript level of alpha 2 type I collagen and tissue inhibitor of metalloproteinases-1, and suppressed expression and activity of matrix metalloproteinases in wild-type SMC. However, these effects of TGF-beta were diminished in null SMC. Our findings altogether show that the loss of Smad3 pathway causes enhanced neointimal hyperplasia on injury through modulation of growth and matrix regulation in vascular SMC. These results indicate a vasculoprotective role of endogenous Smad3 in response to injury.

The CpG motif in DNA plays a critical role in immunity via modulating the Th1/Th2 balance. In B cells, CpG-containing oligodcoxynucleotides (CpG ODNs) inhibit IL-4-mediated class switch recombination (CSR) to IgG1 and IgE through inhibition of the germline transcription (GLT) of these isotypes. However, the molecular mechanism of this inhibitory effect remains elusive. We showed here that Id2 and Bc16, both of which inhibit IgE GLT and CSR, are not involved in this inhibitory pathway. We demonstrated that there is reduced activity of NFkappaB binding to the IgE promoter and a reduction of Irf4 protein in CpG ODN-treated B cells. These data indicate the critical role of NFkappaB and Irf4 in the regulation of IgE CSR through actions downstream of CpG signaling. (C) 2005 Elsevier Inc. All rights reserved.

Marginal zone (MZ)-B cells participate in very early immune responses and play a pivotal role in the first-line of defense against blood-borne Ags including bacterial LPS. Since splenic B cells from c-fos transgenic (H2-c-fos) mice are hyper-sensitive to LPS stimulation, we examined LPS-sensitivity of MZ-B cells in the spleen of H2-c-fos mice. Here, we show that proliferation of MZ-B cells from H2-c-fos mice stimulated with LPS was larger than that from control mice. Proliferation and IgM production of the H2-c-fos MZ-B cells were also larger than those of splenic follicular (FO)-B cells from the 142-c-fos mice, suggesting that c-fos overexpression augments LPS-sensitivity of MZ-B cells more than that of FO-B cells. Furthermore, the number of MZ-B cells but not that of FO-B cells in the spleen of H2-c-fos mice was two- to three-fold larger than that in control littermates. The number of transitional type II (T2)-B cells in H2-c-fos mice was also larger than that of control littermates. However, the number of transitional type I (T1)-B cells in the spleen of H2-c-fos mice was not larger than that of control mice. Moreover, this c-fos effect on differentiation of MZ-B cells was intrinsic in B cells by the competitive repopulation assay with hematopoietic stem cells of H2-c-fos and control mice. These results suggest that c-fos overexpression in B cells augments differentiation and accumulation of MZ-B cells. (c) 2004 Elsevier Ltd. All rights reserved.

The CpG motif in DNA plays a critical role in immunity via modulating the Th1/Th2 balance. In B cells, CpG-containing oligodcoxynucleotides (CpG ODNs) inhibit IL-4-mediated class switch recombination (CSR) to IgG1 and IgE through inhibition of the germline transcription (GLT) of these isotypes. However, the molecular mechanism of this inhibitory effect remains elusive. We showed here that Id2 and Bc16, both of which inhibit IgE GLT and CSR, are not involved in this inhibitory pathway. We demonstrated that there is reduced activity of NFkappaB binding to the IgE promoter and a reduction of Irf4 protein in CpG ODN-treated B cells. These data indicate the critical role of NFkappaB and Irf4 in the regulation of IgE CSR through actions downstream of CpG signaling. (C) 2005 Elsevier Inc. All rights reserved.