A C Gavino1, K Nahmod2, U Bharadwaj3, G Makedonas2, D J Tweardy3,4,5. 1. Section of Immunology, Allergy and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. 2. Center for Human Immunobiology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. 3. Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. 4. Department of Cellular and Molecular Biology, Baylor College of Medicine, Houston, TX, USA. 5. Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
Abstract
BACKGROUND: STAT3 drives development of Th17 cells and cytokine production by Th2 and Th17 cells, which contribute to asthma. Alternative asthma treatments are needed, especially for the Th17 phenotype. We sought to determine whether C188-9, a small-molecule STAT3 inhibitor, can block Th2 and Th17 cell expansion and cytokine production to prevent house dust mite (HDM)-induced airway inflammation and remodeling. METHODS: Three groups of C57BL/6 mice were treated intranasally (IN) and intraperitoneally (IP) daily for 3 weeks with the following: (i) vehicle 1 IN and vehicle 2 IP, (ii) HDM IN and vehicle 2 IP, or (iii) HDM IN and C188-9 IP. Sections of lung were stained with Alcian Blue/PAS and examined microscopically. Total (t) STAT3, STAT3 phosphorylated on Y705 (pSTAT3), IL-17, IL-13, IL-5, and IL-4 levels were measured in lung protein extracts and serum using Luminex beads. Frequencies of Th2-type and Th17-type lymphocytes were assessed in lungs and bronchoalveolar lavage fluid (BALF) by multiparametric flow cytometry. RESULTS: HDM inhalation markedly increased airway goblet cell numbers and thickness of the epithelium and subepithelial smooth muscle layer, which was accompanied in the whole lung by increased pSTAT3, IL-4, IL-5, IL-13, and IL-17, and % CD4+ T cells that produce IL-5, IL-13, and IL-17. HDM inhalation also increased serum IL-4 and IL-17 levels and increased BALF % CD4+ T cells that produce IL-5 and IL-13. Remarkably, treatment with C188-9 normalized each endpoint. CONCLUSION: HDM-induced airway inflammation, remodeling, and Th2/Th17-type cell accumulation involve STAT3 activation that can be prevented by C188-9 treatment.
BACKGROUND:STAT3 drives development of Th17 cells and cytokine production by Th2 and Th17 cells, which contribute to asthma. Alternative asthma treatments are needed, especially for the Th17 phenotype. We sought to determine whether C188-9, a small-molecule STAT3 inhibitor, can block Th2 and Th17 cell expansion and cytokine production to prevent house dust mite (HDM)-induced airway inflammation and remodeling. METHODS: Three groups of C57BL/6 mice were treated intranasally (IN) and intraperitoneally (IP) daily for 3 weeks with the following: (i) vehicle 1 IN and vehicle 2 IP, (ii) HDM IN and vehicle 2 IP, or (iii) HDM IN and C188-9 IP. Sections of lung were stained with Alcian Blue/PAS and examined microscopically. Total (t) STAT3, STAT3 phosphorylated on Y705 (pSTAT3), IL-17, IL-13, IL-5, and IL-4 levels were measured in lung protein extracts and serum using Luminex beads. Frequencies of Th2-type and Th17-type lymphocytes were assessed in lungs and bronchoalveolar lavage fluid (BALF) by multiparametric flow cytometry. RESULTS: HDM inhalation markedly increased airway goblet cell numbers and thickness of the epithelium and subepithelial smooth muscle layer, which was accompanied in the whole lung by increased pSTAT3, IL-4, IL-5, IL-13, and IL-17, and % CD4+ T cells that produce IL-5, IL-13, and IL-17. HDM inhalation also increased serum IL-4 and IL-17 levels and increased BALF % CD4+ T cells that produce IL-5 and IL-13. Remarkably, treatment with C188-9 normalized each endpoint. CONCLUSION: HDM-induced airway inflammation, remodeling, and Th2/Th17-type cell accumulation involve STAT3 activation that can be prevented by C188-9 treatment.
Authors: J Morgan Knight; Pijus Mandal; Pietro Morlacchi; Garbo Mak; Evan Li; Matthew Madison; Cameron Landers; Brandon Saxton; Ed Felix; Brian Gilbert; Joel Sederstrom; Atul Varadhachary; Melissa M Singh; Dev Chatterjee; David B Corry; John S McMurray Journal: J Biol Chem Date: 2018-05-08 Impact factor: 5.157
Authors: Kwang Hwa Jung; Wonbeak Yoo; Heather L Stevenson; Dipti Deshpande; Hong Shen; Mihai Gagea; Suk-Young Yoo; Jing Wang; T Kris Eckols; Uddalak Bharadwaj; David J Tweardy; Laura Beretta Journal: Clin Cancer Res Date: 2017-05-22 Impact factor: 12.531
Authors: Dave Francisco; Ying Wang; Michelle Conway; Audriana N Hurbon; Alane B C Dy; Kenneth J Addison; Hong W Chu; Dennis R Voelker; Julie G Ledford; Monica Kraft Journal: J Immunol Date: 2020-04-03 Impact factor: 5.422