Duran Anyelo, Valero Nereida, Mosquera Jesús, Fuenmayor Edgard, Alvarez-Mon Melchor
Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela; Cátedra de Bioquímica General, Escuela de Bioanálisis, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela; Sociedad Venezolana de Microbiología, Venezuela.
Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela; Sociedad Venezolana de Microbiología, Venezuela.
Life Sci. 2017 Dec 15;191:180-185. doi: 10.1016/j.lfs.2017.10.027. Epub 2017 Oct 18.
The epidermal growth factor receptor (EGFR) and nucleotide-binding and oligomerization-domain containing 2 (NOD2) are important in cancer and in microbial recognition, respectively. These molecules trigger intracellular signaling pathways inducing the expression of inflammatory genes by NF-kB translocation. Gefitinib (GBTC) and pyrrolidine dithiocarbamate (PDTC) are capable of inhibiting EGFR/NOD2 and NF-kB, respectively. In earlier stages of dengue virus (DENV) infection, monocytes are capable of sustaining viral replication and increasing cytokine production, suggesting that monocyte/macrophages play an important role in early DENV replication. GBTC and PDTC have not been used to modify the pathogenesis of DENV in infected cells. This study was aimed to determine the effect of GBTC and PDTC on viral replication and cytokine production in DENV serotype 2 (DENV2)-infected human monocyte cultures.
GBTC and PDTC were used to inhibit EGFR/NOD2 and NF-kB, respectively. Cytokine production was measured by ELISA and viral replication by plaque forming unit assay.
Increased DENV2 replication and anti-viral cytokine production (IFN-α/β, TNF-α, IL-12 and IL-18) in infected cultures were found. These parameters were decreased after EGFR/NOD2 or NF-kB inhibitions.
The inhibitory effects of GBTC and PDTC on viral replication and cytokine production can be beneficial in the treatment of patients infected by dengue and suggest a possible role of EGFR/NOD2 receptors and NF-kB in dengue pathogenesis.
表皮生长因子受体（EGFR）和含核苷酸结合寡聚化结构域2（NOD2）分别在癌症和微生物识别中起重要作用。这些分子触发细胞内信号通路，通过核因子κB（NF-κB）易位诱导炎症基因表达。吉非替尼（GBTC）和吡咯烷二硫代氨基甲酸盐（PDTC）分别能够抑制EGFR/NOD2和NF-κB。在登革病毒（DENV）感染的早期阶段，单核细胞能够维持病毒复制并增加细胞因子产生，这表明单核细胞/巨噬细胞在早期DENV复制中起重要作用。GBTC和PDTC尚未用于改变感染细胞中DENV的发病机制。本研究旨在确定GBTC和PDTC对2型登革病毒（DENV2）感染的人单核细胞培养物中病毒复制和细胞因子产生的影响。
GBTC和PDTC分别用于抑制EGFR/NOD2和NF-κB。通过酶联免疫吸附测定（ELISA）测量细胞因子产生，通过蚀斑形成单位测定测量病毒复制。
在感染的培养物中发现DENV2复制增加和抗病毒细胞因子产生（IFN-α/β、TNF-α、IL-12和IL-18）增加。在EGFR/NOD2或NF-κB抑制后，这些参数降低。
GBTC和PDTC对病毒复制和细胞因子产生的抑制作用可能有利于登革热感染患者的治疗，并提示EGFR/NOD2受体和NF-κB在登革热发病机制中可能起作用。
