The modulation of endoplasmic reticulum stress by chemical chaperone upregulates immune negative cytokine IL-35 in apolipoprotein E-deficient mice.
Interleukin (IL)-35 is a newly identified immune negative molecule which is secreted by CD4(+)Foxp3(+) T regulatory cells (Tregs) and contributes to their suppressive capacity. Early data have shown that IL-35 inhibits development of several autoimmune diseases. However, the role of IL-35 in atherosclerosis, a lipid-driven chronic inflammatory disease in arterial wall, remains to be investigated. Here, we found that IL-35 was involved in atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice. ApoE(-/-) mice with established atherosclerotic lesion displayed a lower level of IL-35 compared to age-matched wild type C57BL/6 mice without plaque. However, IL-35 expression increased significantly in ApoE(-/-) mice with attenuated plaque. More importantly, we found that modulation of ER stress treated by chemical chaperone, 4-Phenyl butyric acid (PBA) in vivo, mainly upregulated immune negative regulating molecule IL-35, as well as IL-10 and Foxp3, accompanied by increased Tregs. However, no obvious impact on pro-inflammatory molecules such as TNF-α, IFN-γ, IL-17 and IL-23 was observed, which provides new insight into the benefit of ER stress recovery from attenuated plaque. Our results suggest that IL-35 might have a potential value for atherosclerotic therapy.
Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, China.
Bo
B
Wang
Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, China.
Shen
S
Dai
Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, China.
Zhaojing
Z
Dong
Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, China.
Yue
Y
Sun
Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, China.
Xingguo
X
Song
Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, China.
Chun
C
Guo
Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, China.
Faliang
F
Zhu
Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, China.
Qun
Q
Wang
Department of Immunology, Shandong University School of Medicine, Jinan, Shandong, China.
Lining
L
Zhang
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
D001057:Apolipoproteins E; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; C569375:interleukin-35, mouse; D007371:Interferon-gamma