title: IL-6 receptor-mediated lung Th2 cytokine networking in silica-induced pulmonary fibrosis.
abstract: Pulmonary silicosis is a deadly disease which kills thousands of people every year worldwide. The disease initially develops as an inflammatory response with recruitment of inflammatory cells into the lung controlled by multiple cytokines. The question whether these cytokines exert biological functions through signal transducing pathway remains unanswered along with the potential role of interleukin-6 receptor α (IL-6Rα) in regulating inflammatory cytokines. We aimed to assess the status of signal transducers and activator of transcription (Stat3), suppressor of cytokine signalling 3(Socs3) and inflammatory cytokines in airways of silica-exposed mice, and their relationship with IL-6Rα. Silica-exposed and silica-exposed IL-6Rα gene knockdown Balb/c mice were used in the study. Lung function was measured by plethysmography, mRNA expression of cytokines and signal molecules by qRT(2)-PCR and lung architecture by histopathology; T helper cell-type 2 (Th2) cytokines in broncho-alveolar lavage fluids were evaluated by ELISA and hydroxyproline in lung by colorimetry. Elevated levels of collagen deposition, signs of lung fibrosis, infiltration of inflammatory cells and presence of exfoliated mucosa in the lung of silica-exposed mice with concurrent increase in methacholine-induced specific resistance of airways were observed on day 60 post-exposure. In parallel, heightened expression of Th2 cytokines (IL-4, IL-5, IL-6) and signal molecules (Stat3 and Socs3) were observed in the airways of silica-exposed mice. Th1 (IL-1β and TNF-α) cytokines are underexpressed in majority of the airways tissues of silica-exposed mice. Silencing IL-6Rα in lung of silica-exposed mice down regulated the hypermorphic mRNA pool of potential Th2 cytokines and signal molecules. Hypermorphic expression of Th2 cytokines and signal molecules in airways of silica-exposed mice are mediated through IL-6Rα.
authors.affiliation: Immunobiology Division, Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow, 226001, India.
authors.forename: Shambhoo Sharan
authors.initials: SS
authors.lastname: Tripathi
authors.forename: Vani
authors.initials: V
authors.lastname: Mishra
authors.forename: Mamta
authors.initials: M
authors.lastname: Shukla
authors.forename: Mukesh
authors.initials: M
authors.lastname: Verma
authors.forename: Bhushan Pradosh
authors.initials: BP
authors.lastname: Chaudhury
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kumar
authors.forename: Jasmeet Kaur
authors.initials: JK
authors.lastname: Chhabra
authors.forename: Haushila Prasad
authors.initials: HP
authors.lastname: Pandey
authors.forename: Bholanath
authors.initials: B
authors.lastname: Paul
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003124:Colorimetry; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006909:Hydroxyproline / Q000032:analysis / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012822:Silicon Dioxide; D012829:Silicosis / Q000378:metabolism / Q000473:pathology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D012822:Silicon Dioxide; D006909:Hydroxyproline