Targeting PI3K P110δ Pathway to Interfere B-1 Cells Functions and Decrease Activity of Murine Lupus
Date Issued
2010
Date
2010
Author(s)
Chen, Szu-Ying
Abstract
Systemic lupus erythematosus is an autoimmune disease caused by multiple pathogenic factors, such as genetic, hormone, environmental, and different abnormal immune components. Hyperreactivity of B cells, expecially B-1 cells, has been suggested to play a critical role in the development of autoantibodies. Previous studies have illustrated that depravation of B-1 cells was profitable to alleviate the disease aggravation. However, these approaches might result in subsequent unfavorable side-effects. P110δ, a leukocyte-specific catalytic subunit of PI3Ks, are proved to be able to abrogate the maturation of B cell lineages, especially the marginal zone B cell and B-1 cell populations. In this study, we plan to apply IC87114, a highly selective inhibitor of P110δ, to interfere the development of B-1 cells in murine NZB/W F1 model. Furthermore, we also studied the effect of IC87114 on B-1 cells both in vitro and in vivo. First, we found IC87114 could decrease the proliferation of splenocytes, B-1 and B-2 cells in dose-dependent response. The drug could also reduce IL-10 production of peritoneal resident cells and B-1 cells. Next, we treated Balb/c mice with IC87114 by peritoneal injection, the population and the activated level of B cells and T cells were not affected, but the proliferation of peritoneal washout cells were decreased. In murine lupus model, we treated NZB/W F1 mice with IC87114 since 2-months by peritoneal injection. Compared to the control group, we found the anti-ss/ds DNA IgG was decreased significantly in the low dose of IC87114 group. In summary, the P110δ inhibitor can suppress the proliferation and cytokine production of B cells effectively, but it did not affect the population, percentage and the activated manners of immune cells in vivo. In the lupus model, the auto-antibodies are decreased, supporting the notion that the p110δ inhibitor might be a potential therapeutic agent for SLE. Moreover, the evidence that PI3Ks are critical for the maintenance of B-1 cell populations might shed light on future exploring the potential treatment of other diseases associated with B-1 cells, such as certain melanoma, lymphoma, or leukemia.
Subjects
Systemic lupus erythematosus
B-1cells
NZB/W F1
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