17β‐estradiol induces CD40 expression in dendritic cells via MAPK signaling pathways in a minichromosome maintenance protein 6–dependent manner

Abstract

Objective. The human immune system exhibits sexual dimorphism in autoimmune diseases such as systemic lupus erythematosus (SLE). Female sex hormones, including 17␤-estradiol, are strongly implicated in the gender bias in SLE. CD40 is a costimulatory molecule and plays a crucial role in modulating the immune response of effector cells. We have previously shown that 17␤-estradiol up-regulated CD40 expression and altered minichromosome maintenance protein 6 (MCM6) gene expression in dendritic cells (DCs). The mechanism of the correlation between CD40 and MCM6 in the presence of 17␤-estradiol remains unknown. This study was undertaken to elucidate this mechanism and to explain the role of MCM6 in the gender bias in SLE.Methods. Bone marrow-derived DCs transfected with small interfering RNA (siRNA) for MCM6 were treated with 17␤-estradiol in the absence or presence of CpG. The expression levels of costimulatory molecules, activity of MAPKs, and levels of MCM6 protein were measured. Moreover, the functions of DCs, including proliferation, apoptosis, endocytosis, and cytokine production, were analyzed. In addition, levels of messenger RNA for MCM6 were detected in DCs purified from SLE patients.Results. Regardless of the presence or absence of CpG, 17␤-estradiol induced CD40 expression via the activation of p38 and JNK, but not ERK. The activation of p38 and JNK enhanced MCM6 expression, which then induced CD40 expression. Suppression of MCM6 in DCs abolished the up-regulation of 17␤-estradiolinduced CD40 expression. Importantly, MCM6 expression was significantly increased in SLE patients compared with healthy controls.Conclusion. Our findings indicate that 17␤-estradiol induces CD40 expression in DCs via p38 and JNK MAPKs in an MCM6-dependent manner. MCM6 may be a critical mediator of sex-based differences in autoimmune disease.

Dendritic cell recruitment and activation in autoimmunity

“…Immunoglobulin-like transcript (ILT)3 was found decreased in circulating cDCs of SLE patients, associated with increased levels of TNF and type I IFNs [176]. The sex hormone 17b estradiol can induce cDC activation through minichromosome maintenance protein (MCM)6 [177]. Opposite results were described on the effect of complement factor C1q on cDC activation.…”

miR141–CXCL1–CXCR2 Signaling–Induced Treg Recruitment Regulates Metastases and Survival of Non–Small Cell Lung Cancer

“…The method of Western blot analysis was performed as described previously (17). The anti-human c-Jun NH2-terminal kinase (JNK), phos-JNK, p38, phosp38, ERKs, phos-ERK, and GAPDH antibodies for Western blot analysis were from Cell Signaling Technology Inc.…”

MicroRNA‐181a Regulates Local Immune Balance by Inhibiting Proliferation and Immunosuppressive Properties of Mesenchymal Stem Cells

“…The method of Western blotting was performed as described previously [31]. Recombinant human TGF-b was from Peprotech (Rocky Hill, NJ, http://www.peprotech.com), MAPK inhibitor SB203580 was from Alexis Biochemicals Inc. (San Diego, CA, http://www.axxora.com), and SP600125 and PD98059 were from Beyotime (Shanghai, People's Republic of China, http://www.beyotime.com).…”

“…Cell viability was assessed with a Cell Counting Kit (Dojindo Laboratories Inc., Japan), as described previously [31].…”