title: SPA0355 suppresses T-cell responses and reduces airway inflammation in mice.
abstract: In recent studies, SPA0355, a thiourea analog, has been demonstrated to possess strong anti-inflammatory activity. However, the mechanisms underlying the effects of SPA0355 on immune-mediated diseases have not been fully defined. The present study was designed to investigate the immunological and molecular mechanisms by which SPA0355 modulates cluster of differentiation of (CD4)(+) T-cell-mediated immune responses in allergic airway inflammation. In vitro studies have shown that SPA0355 suppresses CD4(+) T-cell activation, proliferation, and differentiation via modulation of T-cell receptor (TCR) signal transduction and cytokine-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Next, we investigated the efficacy of SPA0355 in ovalbumin (OVA)-induced allergic airway inflammation. Intraperitoneal administration of SPA0355 inhibited inflammatory cell recruitment into the airways as well as the production of Th2 cytokines in bronchoalveolar fluid and suppressed OVA-induced IgE production in serum. Additionally, SPA0355 suppressed mucin production and smooth muscle hypertrophy and prevented the development of airway hyperresponsiveness. Given that allergic airway inflammation is mainly driven by Th2 cell responses, it is highly possible that the defects in CD4(+) T-cell activation and Th2 cell differentiation in the draining lymph nodes and suppressed NF-κB activation in the lungs of SPA0355-treated mice illustrate an immunological mechanism of the preventive effect of SPA0355 on the aforementioned asthmatic characteristics. Collectively, our results suggest that SPA0355 directly modulates Th1 and Th2 responses through the suppression of multiple signaling pathways triggered by TCR or cytokine receptor stimulation, and that SPA0355 has protective effects in a murine model of allergic airway inflammation.
authors.affiliation: Departments of Biochemistry National University Medical School, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Jang
authors.affiliation: College of Pharmacy, Sookmyung Women׳s University, 52 Hyochangwon-gil, Yongsan-gu, Seoul 140-742, Republic of Korea.
authors.forename: Raok
authors.initials: R
authors.lastname: Jeon
authors.affiliation: Division of Biotechnology, College of Environmental and Bioresource Sciences, Chonbuk National University, Iksan, Jeonbuk 570-752, Republic of Korea.
authors.forename: Kyung-Won
authors.initials: KW
authors.lastname: Kang
authors.affiliation: Departments of Biochemistry National University Medical School, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Song
authors.affiliation: Departments of Anatomy, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Sookmyung Women׳s University, 52 Hyochangwon-gil, Yongsan-gu, Seoul 140-742, Republic of Korea.
authors.forename: Eun
authors.initials: E
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Sookmyung Women׳s University, 52 Hyochangwon-gil, Yongsan-gu, Seoul 140-742, Republic of Korea.
authors.forename: Jae-Ha
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: Division of Biotechnology, College of Environmental and Bioresource Sciences, Chonbuk National University, Iksan, Jeonbuk 570-752, Republic of Korea. Electronic address: leesangm@jbnu.ac.kr.
authors.forename: Sang-Myeong
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Departments of Biochemistry National University Medical School, Jeonju, Jeonbuk 561-756, Republic of Korea. Electronic address: bhpark@jbnu.ac.kr.
authors.forename: Byung-Hyun
authors.initials: BH
authors.lastname: Park
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D048588:Benzoxazines / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D048588:Benzoxazines; D016207:Cytokines; D007166:Immunosuppressive Agents; D009077:Mucins; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; C570784:SPA0355; D010047:Ovalbumin; D013890:Thiourea
keywords: Allergic airway inflammation; SPA0355; T-cell response; Th2 cytokine