Activation of the Liver X Receptor Inhibits Th17 and Th1 Responses in Behcet’s Disease and Vogt-Koyanagi-Harada Disease

Abstract

Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome are two intraocular inflammatory diseases that are caused by an aberrant T lymphocyte response. Th17 cells, mainly producing the cytokine IL-17, and Th1 cells, characterized by the production of the index cytokine IFN-γ, are the CD4(+) T lymphocyte subsets implicated in the pathogenesis of both BD and VKH. Suppressing the excessive response of these Th17 and Th1 cells has been reported to be an effective therapeutic approach to treat these patients and continuous efforts are being undertaken to find new methods to modulate the function of these cells. Evidence is emerging that the Liver X receptor (LXR) is an important regulator of inflammatory and immune responses and the study reported here was designed to investigate the role of LXR activation in BD and VKH. Here we demonstrate that the frequency of Th17 and Th1 cells along with the relevant cytokines IL-17, IFN-γ and corresponding transcriptional factors RORC, T-bet were all decreased following LXR activation by the agonist GW3965. LXR controlled the expression of inflammatory cytokines through an effect on NF-kappa B (NFκb) phosphorylation. Data from our study provide evidence for an association between a decreased LXR expression and disease activity in both BD and VKH, due to the fact that a lower LXR activation may result in an enhanced Th1 and Th17 immune response. Our study suggests that enhancing LXR activation may offer a potential therapeutic approach targeting aberrant immune responses by inhibiting Th1 and Th17 cell responses.

Liver X receptors in immune cell function in humans

“…Additionally, the ability of LXRs to reduce proliferation is restricted to that induced by αCD3 alone, the addition of co-stimulatory molecule αCD28 being sufficient to restore full proliferative capacity. This could explain the discrepancy between reports showing LXR activation to have no effect [35] or inhibit [31,34] proliferation of human CD4 + T-cells, indicating that LXR anti-proliferative effects are highly sensitive to the potency of T-cell stimulation. In contrast with T cells, LXR activation in B-cells from healthy individuals has no effects on proliferation or survival, although it inhibits IgE secretion [36].…”

“…LXRs also inhibit interleukin (IL)-17 production [30,31], via LXR induction of SREBP1, which binds the IL-17 promoter and antagonizes a positive regulator of transcription, the aryl hydrocarbon receptor (Ahr) [30]. This results in the inhibition of T H 17 cell differentiation and activity, a T-cell lineage implicated in numerous autoimmune disorders [32].…”

“…Reciprocally, TCR activation increased expression of SULT2B1, a sulfotransferase which modifies endogenous LXR ligands to an inactive form, thereby reducing LXR activity [33]. In contrast, apoptosis is not induced in human T-cells [31,33,34]. Additionally, the ability of LXRs to reduce proliferation is restricted to that induced by αCD3 alone, the addition of co-stimulatory molecule αCD28 being sufficient to restore full proliferative capacity.…”

Liver X receptors agonist GW3965 re-sensitizes gefitinib-resistant human non-small cell lung cancer cell to gefitinib treatment by inhibiting NF-κB in vitro

“…LXR could be activated by the agonist GW3965 [22]. And LXR agonist could reverse the increase of NF-κB-p65 protein expression [23].…”

Disabled-2 (DAB2) Overexpression Inhibits Monocyte-Derived Dendritic Cells' Function in Vogt-Koyanagi-Harada Disease

“…7,8 Recent findings have demonstrated that dendritic cells (DCs), T helper type 1 (Th1)/Th17 cells, and their associated cytokines may play a crucial role in this disease. 4,9 DCs, which connect specific adaptive immune responses with innate immune responses as professional antigen presenting cells, are important in mediating T-cell differentiation. 10,11 The high surface marker expression and inflammatory factor secretion of DCs result in a cascade of immune responses.…”