Potential Relevance of Cytoplasmic Viral Sensors and Related Regulators Involving Innate Immunity in Antiviral Response

@article{citeulike:2806609, abstract = {Background \& Aims: Clinical significance of molecules involving innate immunity in treatment response remains unclear. The aim is to elucidate the mechanisms underlying resistance to antiviral therapy and predictive usefulness of gene quantification in chronic hepatitis C (CH-C). Methods: We conducted a human study in 74 CH-C patients treated with pegylated interferon [alpha]-2b and ribavirin and 5 nonviral control patients. Expression of viral sensors, adaptor molecule, related ubiquitin E3-ligase, and modulators were quantified. Results: Hepatic RIG-I, MDA5, LGP2, ISG15, and USP18 in CH-C patients were up-regulated at 2- to 8-fold compared with nonhepatitis C virus patients with a relatively constitutive Cardif. Hepatic RIG-I, MDA5, and LGP2 were significantly up-regulated in nonvirologic responders (NVR) compared with transient (TR) or sustained virologic responders (SVR). Cardif and RNF125 were negatively correlated with RIG-I and significantly suppressed in NVR. Differences among clinical responses in RIG-I/Cardif and RIG-I/RNF125 ratios were conspicuous (NVR/TR/SVR = 1.3:0.6:0.4 and 2.3:1.3:0.8, respectively). Like viral sensors, ISG15 and USP18 were significantly up-regulated in NVR (4-fold and 2.3-fold, respectively). Multivariate and receiver operator characteristic analyses revealed higher RIG-I/Cardif ratio, ISG15, and USP18 predicted NVR. Lower Cardif in NVR was confirmed by its protein level in Western blot. Also, transcriptional responses in peripheral blood mononuclear cells to the therapy were rapid and strong except for Cardif in not only a positive (RIG-I, ISG15, and USP18) but also in a negative regulatory manner (RNF125). Conclusions: NVR may have adopted a different equilibrium in their innate immune response. High RIG-I/Cardif and RIG-I/RNF125 ratios and ISG15 and USP18 are useful in identifying NVR.}, author = {Asahina, Yasuhiro and Izumi, Namiki and Hirayama, Itsuko and Tanaka, Tomohiro and Sato, Mitsuaki and Yasui, Yutaka and Komatsu, Nobutoshi and Umeda, Naoki and Hosokawa, Takanori and Ueda, Ken and Tsuchiya, Kaoru and Nakanishi, Hiroyuki and Itakura, Jun and Kurosaki, Masayuki and Enomoto, Nobuyuki and Tasaka, Megumi and Sakamoto, Naoya and Miyake, Shozo }, citeulike-article-id = {2806609}, doi = {10.1053/j.gastro.2008.02.019}, journal = {Gastroenterology}, month = {May}, number = {5}, pages = {1396--1405}, posted-at = {2008-05-17 09:32:54}, priority = {2}, title = {Potential Relevance of Cytoplasmic Viral Sensors and Related Regulators Involving Innate Immunity in Antiviral Response}, url = {http://dx.doi.org/10.1053/j.gastro.2008.02.019}, volume = {134}, year = {2008} }

TY - JOUR ID - citeulike:2806609 L3 - citeulike-article-id:2806609 TI - Potential Relevance of Cytoplasmic Viral Sensors and Related Regulators Involving Innate Immunity in Antiviral Response JF - Gastroenterology VL - 134 IS - 5 SP - 1396 EP - 1405 N2 - Background & Aims: Clinical significance of molecules involving innate immunity in treatment response remains unclear. The aim is to elucidate the mechanisms underlying resistance to antiviral therapy and predictive usefulness of gene quantification in chronic hepatitis C (CH-C). Methods: We conducted a human study in 74 CH-C patients treated with pegylated interferon [alpha]-2b and ribavirin and 5 nonviral control patients. Expression of viral sensors, adaptor molecule, related ubiquitin E3-ligase, and modulators were quantified. Results: Hepatic RIG-I, MDA5, LGP2, ISG15, and USP18 in CH-C patients were up-regulated at 2- to 8-fold compared with nonhepatitis C virus patients with a relatively constitutive Cardif. Hepatic RIG-I, MDA5, and LGP2 were significantly up-regulated in nonvirologic responders (NVR) compared with transient (TR) or sustained virologic responders (SVR). Cardif and RNF125 were negatively correlated with RIG-I and significantly suppressed in NVR. Differences among clinical responses in RIG-I/Cardif and RIG-I/RNF125 ratios were conspicuous (NVR/TR/SVR = 1.3:0.6:0.4 and 2.3:1.3:0.8, respectively). Like viral sensors, ISG15 and USP18 were significantly up-regulated in NVR (4-fold and 2.3-fold, respectively). Multivariate and receiver operator characteristic analyses revealed higher RIG-I/Cardif ratio, ISG15, and USP18 predicted NVR. Lower Cardif in NVR was confirmed by its protein level in Western blot. Also, transcriptional responses in peripheral blood mononuclear cells to the therapy were rapid and strong except for Cardif in not only a positive (RIG-I, ISG15, and USP18) but also in a negative regulatory manner (RNF125). Conclusions: NVR may have adopted a different equilibrium in their innate immune response. High RIG-I/Cardif and RIG-I/RNF125 ratios and ISG15 and USP18 are useful in identifying NVR. AU - Asahina, Yasuhiro AU - Izumi, Namiki AU - Hirayama, Itsuko AU - Tanaka, Tomohiro AU - Sato, Mitsuaki AU - Yasui, Yutaka AU - Komatsu, Nobutoshi AU - Umeda, Naoki AU - Hosokawa, Takanori AU - Ueda, Ken AU - Tsuchiya, Kaoru AU - Nakanishi, Hiroyuki AU - Itakura, Jun AU - Kurosaki, Masayuki AU - Enomoto, Nobuyuki AU - Tasaka, Megumi AU - Sakamoto, Naoya AU - Miyake, Shozo PY - 2008/05// UR - http://dx.doi.org/10.1053/j.gastro.2008.02.019 ER -