Hypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha.
Hypoxia-induced mitogenic factor (HIMF), also called FIZZ1 or RELMalpha, was a newly found cytokine. Hypoxia caused robust HIMF induction in the lung, and HIMF has potent pulmonary vasoconstrictive, proliferative, and angiogenic properties. To investigate the role of HIMF in lung development, we determined its spatial and temporal expression. From embryonic day (E)16 to postnatal day (P)28, HIMF was strongly expressed in the cytoplasm of bronchial epithelial cells, type II cells, endothelial cells, and primitive mesenchymal cells. Treatment with HIMF resulted in a significant reduction of apoptosis in cultured embryonic lung, thus revealing a previously unknown function of HIMF. Because HIMF gene is upregulated by hypoxia and contains a hypoxia-inducible transcription factor (HIF) binding site, we subsequently investigated whether HIMF was coexpressed with HIF-2alpha or HIF-1alpha. HIF-1alpha expression was temporally distinct from HIMF expression. In contrast, HIF-2alpha was present in endothelial cells, bronchial epithelial cells, and type II cells from E18 to P28. Thus, HIMF and HIF-2alpha were temporally and spatially coexpressed in the developing lung. These results indicate a role for HIMF in lung development, possibly under the control of HIF-2, and suggest that HIMF regulates apoptosis and may participate in lung alveolarization and maturation.
Wagner
Klaus F
KF
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Hellberg
Ann-Katrin
AK
Balenger
Susan
S
Depping
Reinhard
R
Dodd-O
Jeffrey
J
Johns
Roger A
RA
Li
Dechun
D
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000196:embryology*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D020932:Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D011506:Proteins; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D020932:Nerve Growth Factor; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C413576:Retnla protein, mouse