title: Glucocorticoids potentiate IL-6-induced SP-B expression in H441 cells by enhancing the JAK-STAT signaling pathway.
abstract: The respiratory distress syndrome (RDS) contributes to perinatal morbidity and mortality associated with preterm birth. Surfactant protein B (SP-B) is decreased in RDS. Both maternal antenatal steroid administration and chorioamnionitis reduce the incidence and severity of RDS. An important mediator in chorioamnionitis is IL-6 using the JAK-STAT signaling pathway for signal transduction. We hypothesized that the steroids, betamethasone (BTM) and dexamethasone (DXM), and IL-6 had synergistic effects on SP-B gene expression and STAT3 phosphorylation in H441 cells. DXM and BTM increased SP-B mRNA levels by 16.5 (13.3)-fold and IL-6 alone by 2.3-fold. After 48-h exposure of cells to DXM or BTM, IL-6 caused a significantly greater increase in SP-B mRNA levels (28.1-fold) than IL-6 or glucocorticoids alone. Whereas IL-6 stimulated tyrosine phosphorylation of STAT3 in a time- and dose-dependent way, DXM and BTM had no effect on STAT3 phosphorylation. Both DXM and BTM could potentiate IL-6-induced phosphorylation of STAT3. The synergism of glucocorticoids and IL-6 on SP-B gene expression and the effect of glucocorticoids on IL-6-induced STAT3 phosphorylation could be blocked by a JAK inhibitor. Expression level analysis showed that glucocorticoids increased the expression of the IL-6-binding α-subunit receptor (IL-6R) on mRNA and protein level. Our findings could represent an example of a pulmonary regulation system in which one role of glucocorticoids is to increase the effect of a cytokine by upregulation of its receptor. The described in vitro interaction of IL-6 and glucocorticoids could help explain the clinical observation that prenatal inflammation in preterm babies with antenatal steroid administration can attenuate severity of RDS.
authors.affiliation: Children's Hospital, Univ. of Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ladenburger
authors.forename: Matthias
authors.initials: M
authors.lastname: Seehase
authors.forename: Boris W
authors.initials: BW
authors.lastname: Kramer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Thomas
authors.forename: Johannes
authors.initials: J
authors.lastname: Wirbelauer
authors.forename: Christian P
authors.initials: CP
authors.lastname: Speer
authors.forename: Steffen
authors.initials: S
authors.lastname: Kunzmann
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001623:Betamethasone / Q000494:pharmacology*; D015153:Blotting, Western; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D037701:Pulmonary Surfactant-Associated Protein B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D037701:Pulmonary Surfactant-Associated Protein B; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D003907:Dexamethasone; D001623:Betamethasone; C507904:JAK1 protein, human; D053613:Janus Kinase 1