The Role of Glycoprotein 130 Family of Cytokines in Fetal Rat Lung Development

Abstract

The glycoprotein 130 (gp130) dependent family of cytokines comprises interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) and oncostatin M (OSM). These cytokines share the membrane gp130 as a common signal transducer. Recently, it was demonstrated that IL-6 promotes, whereas LIF inhibits fetal lung branching. Thus, in this study, the effects on fetal lung morphogenesis of the other classical members of the gp130-type cytokines (IL-11, CLC, CNTF, CT-1 and OSM) were investigated. We also provide the first description of these cytokines and their common gp130 receptor protein expression patterns during rat lung development. Fetal rat lung explants were cultured in vitro with increasing concentrations of IL-11, CLC, CNTF, CT-1 and OSM. Treated lung explants were morphometrically analyzed and assessed for MAPK, PI3K/AKT and STAT3 signaling modifications. IL-11, which similarly to IL-6 acts through a gp130 homodimer receptor, significantly stimulated lung growth via p38 phosphorylation. On the other hand, CLC, CNTF, CT-1 and OSM, whose receptors are gp130 heterodimers, inhibited lung growth acting in different signal-transducing pathways. Thus, the present study demonstrated that although cytokines of the gp130 family share a common signal transducer, there are specific biological activities for each cytokine on lung development. Indeed, cytokine signaling through gp130 homodimers stimulate, whereas cytokine signaling through gp130 heterodimers inhibit lung branching.

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia

“…Herein, it is demonstrated that precise regulation of STAT signaling is necessary for proper fetal lung growth during early development, revealing an unanticipated role of STAT signaling during lung branching morphogenesis. Even though STAT transcription factors have been largely overlooked in lung development, STAT3 has been previously implicated in the regulation of developmental processes [14][15][16][17], namely lung branching [26,27,36], which is consistent with our findings. More importantly, we show that modulation of fetal lung growth can be achieved by conditionally targeting STAT signaling, though the detailed mechanistic interactions are yet to be fully defined.…”

“…Recently, Carraro et al suggested that stabilization of STAT3 RNA expression during the pseudoglandular stage may be important for correct branching morphogenesis [36]. Previous studies have also implicated STAT3 in lung branching morphogenesis [26], and a consistent downstream of STAT3 activation was observed in response to the inhibitory actions of cytokines on fetal lung branching [27].…”

“…Immunostaining was performed on paraformaldehyde-fixed and paraffin-embedded excised lungs and embryos of different gestational ages (15.5 -21.5 dpc) as previously described [26][27][28]. Primary antibodies for STAT1 (1:200, Abcam Inc., UK), STAT2 (1:50, Abcam Inc.), STAT3 (1:50, Cell Signaling Technology Inc., USA), STAT4 (1:50, Cell Signaling Technology Inc.), STAT5 (1:50, Santa Cruz Biotechnology Inc., USA), and STAT6 (1:50, Abcam Inc.) were used.…”

The Role of Ephrins-B1 and -B2 During Fetal Rat Lung Development

“…Many factors that regulate fetal lung branching morphogenesis activate signaling pathways that culminate with MAPK, PI3K/Akt and p38 cascades [30,31,40,41,42]. In the present study, ephrin-B1 was found not to modify the phosphorylated levels of these proteins.…”

Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in Mice

“…Noteworthy transcripts in these categories/pathways included casein kinase 1, epsilon (CSNK1E) (64), mitogenactivated protein kinase 6 (MAPK6; a.k.a. ERK3) (65), mechanistic target of rapamycin (serine/threonine kinase) (MTOR) (66), oncostatin M (OSM) (67,68), TLR6 (69), mucin 20 (MUC20) (70,71), MAD homolog 1 (SMAD1) (72, 73), (74,75), claudin 3 (CLDN3), CLDN4, CLDN5, CLDN7 (76)(77)(78), and lethal giant larvae homolog 2 (Drosphila) (LLGL2) (79,80).…”