Abstract
Endoplasmic reticulum (ER) stress triggers the unfolded protein response (UPR), which has been correlated with enhancedproduction of inflammatory cytokines. Given the important pathogenic roles of macrophages and inflammatory responses in theetiopathogenesis of Behcet’s disease (BD), this study aimed to assess the mRNA expression pattern of genes involved in theUPR pathway in macrophages from smoker and non-smoker BD patients. This case-control study was conducted between 2015and 2016 in Shariati Hospital, Tehran, Iran. Monocytes were enriched from obtained whole blood samples of 10 smokers and 10non-smoker BD patients as well as 10 healthy individuals. Using macrophage-colony stimulating factor (M-CSF), separatedmonocytes were differentiated into macrophages. After total RNA purification and cDNA synthesis, quantification analysis ofUPR genes, including activating transcription factor (ATF) 4, ATF6, X-box binding protein 1 (XBP1), binding immunoglobulinprotein (BIP), C/EBP homologous protein (CHOP), homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERP), and growth arrest and DNA damage-inducible protein (GADD34), was performed using SYBRgreen master mix and real-time PCR. Among the measured genes, HERP mRNA was overexpressed in macrophages from BDpatients in comparison with healthy macrophages. HERP and GADD34 genes were upregulated in smoker BD patients comparedwith non-smoker BD patients as well as healthy subjects. Cigarette smoke can induce UPR gene expression in BD patients. Thealtered UPR gene expression in BD macrophages may contribute to BD pathogenesis.
Highlights
Behcet’s disease (BD), traditionally known as Silk Road disease, is a chronic multisystemic autoimmune disease with relapsing/remitting episodes [1] that manifests most importantly as genital and oral ulcers as well as ocular involvement [2]
To isolate monocytes from peripheral blood mononuclear cells (PBMCs), first, 20 ml peripheral blood was drawn from each participant in tubes containing ethylenediaminetetraacetic acid (EDTA)
The purity of differentiated macrophages was evaluated by flow cytometry, and the results showed that after 7 days of stimulation by macrophage-colony stimulating factor (M-CSF), the cells expressed macrophage markers CD206 and CD163, 91% and 95%, respectively [24]
Summary
Behcet’s disease (BD), traditionally known as Silk Road disease, is a chronic multisystemic autoimmune disease with relapsing/remitting episodes [1] that manifests most importantly as genital and oral ulcers as well as ocular involvement [2]. Concerning the immune system, it has demonstrated that innate inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-12, IL-6, IL-15, IL-23, tumor necrosis factor-alpha (TNF-α), and adaptive cytokines from Th1 helper cells including interferon-gamma (IFN-γ), IL-2, and IL-17 and only IL-13 from Th2 lymphocytes have significant associations with BD pathogenesis. Especially in the expression of innate immunity cytokine profile [8] or the ratio of Th17 to Th1 cells, could be of great importance in the pathogenesis of the disease [9], which is still a controversial topic [6]. Regarding the role of pro-inflammatory cytokines in this disease, BD manifests as inflammation episodes in almost all organs and tissues such as joints, the gastrointestinal tract, and the nervous system, and it affects both arteries and veins [10]. Vasculitis is greatly dependent on macrophage functions in harmony with other immune cells, Th1 cells, Received: 16 November 2019; Accepted: 19 January 2020 65
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