title: Reduced IL-10 production in fetal type II epithelial cells exposed to mechanical stretch is mediated via activation of IL-6-SOCS3 signaling pathway.
abstract: An imbalance between pro-inflammatory and anti-inflammatory cytokines is a key factor in the lung injury of premature infants exposed to mechanical ventilation. Previous studies have shown that lung cells exposed to stretch produces reduced amounts of the anti-inflammatory cytokine IL-10. The objective of these studies was to analyze the signaling mechanisms responsible for the decreased IL-10 production in fetal type II cells exposed to mechanical stretch. Fetal mouse type II epithelial cells isolated at embryonic day 18 were exposed to 20% stretch to simulate lung injury. We show that IL-10 receptor gene expression increased with gestational age. Mechanical stretch decreased not only IL-10 receptor gene expression but also IL-10 secretion. In contrast, mechanical stretch increased release of IL-6. We then investigated IL-10 signaling pathway-associated proteins and found that in wild-type cells, mechanical stretch decreased activation of JAK1 and TYK2 and increased STAT3 and SOCS3 activation. However, opposite effects were found in cells isolated from IL-10 knockout mice. Reduction in IL-6 secretion by stretch was observed in cells isolated from IL-10 null mice. To support the idea that stretch-induced SOCS3 expression via IL-6 leads to reduced IL-10 expression, siRNA-mediated inhibition of SOCS3 restored IL-10 secretion in cells exposed to stretch and decreased IL-6 secretion. Taken together, these studies suggest that the inhibitory effect of mechanical stretch on IL-10 secretion is mediated via activation of IL-6-STAT3-SOCS3 signaling pathway. SOCS3 could be a therapeutic target to increase IL-10 production in lung cells exposed to mechanical injury.
authors.affiliation: Department of Pediatrics, Women & Infants Hospital of Rhode Island and The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hokenson
authors.forename: Yulian
authors.initials: Y
authors.lastname: Wang
authors.forename: Renda L
authors.initials: RL
authors.lastname: Hawwa
authors.forename: Zheping
authors.initials: Z
authors.lastname: Huang
authors.forename: Surendra
authors.initials: S
authors.lastname: Sharma
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchez-Esteban
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D018274:Electroporation; D004847:Epithelial Cells / Q000378:metabolism*; D005333:Fetus / Q000166:cytology* / Q000378:metabolism; D005865:Gestational Age; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016014:Linear Models; D051379:Mice; D018345:Mice, Knockout; D010812:Physical Stimulation; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053701:Receptors, Interleukin-10 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D034741:RNA, Small Interfering; D053701:Receptors, Interleukin-10; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10