A New Role for Conivaptan in Ulcerative Colitis in Mice: Inhibiting Differentiation of CD4+T Cells into Th1 Cells

Abstract

Background: Conivaptan, a nonselective antagonist of vasopressin receptors V1a and V2, is the first drug of this class to be used for treating euvolemic and hypervolemic hyponatremia. Recently, increasing evidence supports the involvement of vasopressin in immune responses.

Aims: In this study, we investigated the effect of conivaptan on the modulation of CD4⁺ T cell homeostasis and the progression of experimental colitis.

Methods: The expression of the V1a receptor on CD4⁺ T cells was detected by immunofluorescence and western blot. The subset of isolated CD4⁺ T cells were examined after arginine vasopressin (AVP) incubation. CD4⁺ T cells were injected into DNBS-induced mice through the tail vein. The severity of colitis was evaluated according to weight, disease activity index (DAI), and morphological injury. Intracellular Ca²⁺ ([Ca²⁺]_i) signaling in CD4⁺ T cells was measured using the Fluo-3 AM loading method. T-bet and IFN-γ mRNAs in the colon were detected by real-time polymerase chain reaction (qPCR).

Results: We found that CD4⁺ T cells expressed the V1a receptor. Activation of the V1a receptor significantly promoted the differentiation of CD4⁺ T cells into T helper 1 (Th1) cells. This process was blocked by conivaptan treatment. However, the activation of the V1a receptor did not evoke an increase in [Ca²⁺]_i in CD4⁺ T cells. Notably, conivaptan markedly alleviated body weight loss, pathological damage, and expression of T-bet and IFN-γ in the colon of DNBS-treated mice.

Conclusions: For the first time, we report that conivaptan attenuated colitis by inhibiting the differentiation of CD4⁺ T cells into Th1 cells. Mechanistically, the anti-inflammatory role of conivaptan is independent of [Ca²⁺]_i.

Keywords: CD4+T cell; Conivaptan; Inflammatory bowel disease; Th1 cell; V1a receptor.