Tumor necrosis factor-alpha and embryonic mouse lung morphogenesis.
The ontogeny of the embryonic and fetal lung involves complex interactions between epithelial and mesenchymal primordia which require a specific program of gene regulation and signal transduction. Past studies in our laboratory using congenic mouse strains indicate that one or more genes which map to the H-2 region of chromosome 17 regulate the rate of lung morphogenesis, defined in this context as differentiative heterochrony among strains. Since hormones and growth factors are the messengers of morphogenesis, it was logical to propose that tumor necrosis factor-alpha (TNF-alpha), a well-characterized cytokine whose gene maps to the D-region of the H-2 complex, is a putative mediator of lung morphogenesis. We investigated this proposition using immunochemical methods and a serumless, chemically defined in vitro model system. Our results demonstrate that: (1) TNF-alpha has a specific spatiotemporal localization, in vivo and in vitro; (2) TNF-alpha receptor, in vivo and in vitro, is localized throughout the embryonic lung; (3) TNF-alpha supplementation in vitro of embryonic lung primordia has a marked dose-dependent, stimulatory effect on branching morphogenesis and surfactant-associated protein (SP-A) expression; (4) multiple immunoreactive proteins, including 17, 26, and 68 kDa species, are expressed during development in vivo, and a subset of these are expressed in vitro; and (5) both time- and glucocorticoid-dependent changes occur in the in vivo expression pattern of TNF-alpha immunoreactive proteins after 4 and 7 days in vitro, including the up-regulation of a novel 40 kDa protein. Given that glucocorticoids (CORT) regulate TNF-alpha expression and TNF-alpha's ability to stimulate pulmonary morphodifferentiation and histodifferentiation, we conclude that TNF-alpha is an autocrine/paracrine pulmonary cytokine, probably a component of the lung morphogenesis pathway regulated by CORT.
Jaskoll
T
T
Laboratory for Developmental Genetics, University of Southern California, Los Angeles 90089-0641.
Boyer
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PD
Melnick
M
M
D000818:Animals; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004627:Embryonic Induction; D005314:Embryonic and Fetal Development / Q000235:genetics; D004848:Epithelium / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005938:Glucocorticoids / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000196:embryology* / Q000648:ultrastructure; D008285:Major Histocompatibility Complex; D008648:Mesoderm / Q000502:physiology; D051379:Mice / Q000196:embryology / Q000235:genetics; D008815:Mice, Inbred Strains; D009024:Morphogenesis / Q000187:drug effects / Q000235:genetics; D009924:Organ Culture Techniques; D011663:Pulmonary Surfactants / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D005938:Glucocorticoids; D011663:Pulmonary Surfactants; D011965:Receptors, Glucocorticoid; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha