Thymulin evokes IL-6-C/EBPbeta regenerative repair and TNF-alpha silencing during endotoxin exposure in fetal lung explants.
Chorioamnionitis is associated with increased risks of perinatal respiratory failure; however, components of the inflammatory acute-phase response are known to actively promote lung maturation. To manipulate this relationship, we examined the effect of the thymic immunomodulator thymulin on fetal lung mesenchyme-epithelial differentiation during exposure to Escherichia coli lipopolysaccharide (LPS). Gestation day 14 fetal rat lung explants were cultured for 96 h at fetal (23 mmHg) or ambient (142 mmHg) Po(2). Airway surface complexity (ASC, perimeter/ radical area(2)) was greater at fetal vs. ambient Po(2); however, exposure to 0.1-50 microg/ml LPS significantly raised ASC at 2 microg/ml in ambient Po(2) explants. LPS (50 microg/ml) depressed ASC in both conditions to untreated ambient Po(2) control values without changes in necrosis or apoptosis. To manipulate LPS-evoked TNF-alpha and IL-6 release, we exposed explants and A549 cells to combinations of 50 microg/ml LPS, 10 microM ZnCl(2), and 0.1-1,000 ng/ml thymulin at either Po(2). Thymulin+Zn(2+) suppressed and potentiated LPS-evoked TNF-alpha and IL-6 release, yielding an IC(50(TNF-alpha)) of 0.5 +/- 0.01 ng/ml and EC(50(IL-6)) of 1.4 +/- 0.3 ng/ml in A549 cells. This was accompanied by activation of the p38 MAPKMAPKAP-K2 pathway with sustained expression of TNF-alpha and IL-6 transcripts at ambient Po(2). LPS+thymulin+Zn(2+)-treated explants showed proliferation of CCAAT-enhancer binding protein-beta (C/EBPbeta) and fibroblast growth factor-9 immunoreactive mesenchyme, which was abolished by IL-6 antisense oligonucleotides. The posttranscriptional suppression of immunogenic TNF-alpha synthesis coupled with raised IL-6 and C/EBPbeta-dependent mesenchyme proliferation suggests a role for bioactive thymulin in regulating regenerative repair in the fetal lung.
Land
Stephen C
SC
Tayside Inst. of Child Health, Maternal and Child Health Sciences, Ninewells Hospital and Medical School, Univ. of Dundee, Dundee, DD1 9SY, UK. s.c.land@dundee.ac.uk
Darakhshan
Froogh
F
D000230:Adenocarcinoma; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D045744:Cell Line, Tumor; D005333:Fetus; D051526:Fibroblast Growth Factor 10; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000196:embryology / Q000276:immunology*; D008648:Mesoderm / Q000166:cytology; D010100:Oxygen / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013935:Thymic Factor, Circulating / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*; D015032:Zinc / Q000494:pharmacology; D000099190:MAP-Kinase-Activated Kinase 2
D000276:Adjuvants, Immunologic; D022782:CCAAT-Enhancer-Binding Protein-beta; D051526:Fibroblast Growth Factor 10; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D010100:Oxygen; D017346:Protein Serine-Threonine Kinases; D013935:Thymic Factor, Circulating; D014409:Tumor Necrosis Factor-alpha; D015032:Zinc; D000099190:MAP-Kinase-Activated Kinase 2; C496459:FGF9 protein, human