Background/Purpose:

The purpose of the present study was to investigate whether ER stress inhibition by 4-phenylbutyric acid (4-PBA) ameliorates lupus manifestations in an experimental lupus model and the effect of ER stress inhibition by 4-PBA on the frequency and function of regulatory T cells (Treg).

Methods:

A murine lupus model was induced through a 4-week treatment with Resiquimod, a toll-like receptor agonist 7. From the 8^th week, the mice were treated with phosphate buffered saline, 4-PBA, and dexamethasone for 4 weeks. The increment of body weight, spleen weight, anti-dsDNA antibody titer, serum cytokines level, and the pathology of glomerulonephritis were analyzed at 12 weeks of age. The population of immune cellular subset, including activated T and B lymphocytes and Treg, and suppressive functions of Treg, were measured.

Results:

4-PBA significantly decreased the level of anti-dsDNA antibodies and serum TNF-¥á in the murine lupus model. A significant decrease in accumulation of immunoglobulin and glomerulonephritis score was also observed in 4-PBA-treated and dexamethasone-treated mice compared to vehicle-treated group. ER stress inhibition decreased the activated T and B lymphocytes population of splenocytes, but the population of Treg was not significantly different between vehicle group and 4-PBA group. However, a markedly enhanced suppressive capacity of Treg was detected in 4-PBA-treated group.

Conclusion:

Our results suggest that ER stress inhibition attenuates disease activity, especially of lupus nephritis, in an experimental model by improving the suppressive capacity of Treg. Thus, reduction of ER stress could be used as a beneficial therapeutic strategy in SLE.