Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine; Division of Molecular Signaling, Department of the Advanced Biomedical Research, University of Yamanashi, Chuo, Yamanashi, Japan.
Division of Molecular Signaling, Department of the Advanced Biomedical Research, University of Yamanashi, Chuo, Yamanashi, Japan.
Int Immunopharmacol. 2019 Aug;73:491-501. doi: 10.1016/j.intimp.2019.05.052. Epub 2019 Jun 4.
Hydrogen sulfide (HS) has emerged as an important biological mediator with numerous pathophysiological roles. One of the well-documented actions of HS is to inhibit immunity, especially cellular immunity. Currently, limited information is available regarding its effects on humoral immunity. Given that HS has reducing activity and that the effector molecules in humoral immunity, such as antibody and complement, contain abundant disulfide bonds that are indispensable for their functions, we speculated that HS might regulate antibody activity via modification of disulfide bonds. Here we addressed this possibility. Exposure of antibodies to HS donors resulted in cleavage of the disulfide bonds between the heavy and light chains of antibodies, which was associated with antibody sulfhydration. Further analysis revealed that HS-treated antibodies exhibited a marked reduction in antigen binding ability. It potently prevented the antibody-mediated agglutination of red blood cells and interrupted aggregation of antibody-coated microspheres. HS also greatly inhibited antibody-induced and complement-mediated cell lysis in glomerular mesangial cells, as well as anti-CD95 IgM antibody-initiated cell apoptosis in Jurkat cells. Moreover, it significantly suppressed the alternative complement activation pathway. Collectively, our results revealed, for the first time, that pharmacologic levels of HS inhibit humoral immune responses via direct sulfhydration of the effector molecules. Our study thus provides novel mechanistic insights into the immunoregulatory actions of HS and suggests that HS may have potential to treat certain humoral immune diseases.
硫化氢 (HS) 已成为具有多种病理生理作用的重要生物介质。HS 的作用之一是抑制免疫，尤其是细胞免疫。目前，关于其对体液免疫的影响的信息有限。鉴于 HS 具有还原活性，并且体液免疫中的效应分子，如抗体和补体，含有丰富的二硫键，这些二硫键对于它们的功能是不可或缺的，我们推测 HS 可能通过修饰二硫键来调节抗体活性。在这里，我们研究了这种可能性。将抗体暴露于 HS 供体中会导致抗体的重链和轻链之间的二硫键断裂，这与抗体的巯基化有关。进一步的分析表明，HS 处理的抗体表现出抗原结合能力的显著降低。它能有效阻止抗体介导的红细胞凝集和抗体包被的微球的聚集。HS 还极大地抑制了肾小球系膜细胞中抗体诱导的和补体介导的细胞裂解，以及 Jurkat 细胞中抗 CD95 IgM 抗体引发的细胞凋亡。此外，它还显著抑制替代补体激活途径。总之，我们的研究结果首次揭示，药理水平的 HS 通过效应分子的直接巯基化抑制体液免疫反应。我们的研究为此提供了 HS 免疫调节作用的新机制见解，并表明 HS 可能有潜力治疗某些体液免疫疾病。
