Leukemia inhibitory factor mRNA expression is upregulated in macrophages and olfactory receptor neurons after target ablation.
After target ablation by olfactory bulbectomy (OBX), the murine olfactory epithelium (OE) undergoes degenerative changes leading to apoptosis of olfactory receptor neurons (ORNs) followed by regenerative changes that include proliferation of progenitor cells leading to neurogenesis and ORN replacement. Macrophages recruited to the OE after OBX are involved in both the degenerative and regenerative processes. Relative quantitative RT-PCR was used to demonstrate that within hours of OBX, mRNAs encoding three key components in the leukemia inhibitory factor (LIF) signaling pathway, including LIF, LIF receptor (LIFR), and STAT3, as well as cyclin D1, a growth factor sensor indicative of progenitor cell transformation, were upregulated. These mRNAs reached peak levels of expression on or before day 3 post-OBX, coincident with the peak time for macrophage recruitment and progenitor cell proliferation. Cells expressing LIF mRNA in the OE of mice at 3 days post-OBX, the time point at which LIF mRNA expression peaked, were identified using non-isotopic in situ hybridization. LIF mRNA was localized in infiltrating macrophages; near-adjacent sections exhibited macrophages immunoreactive for F4/80, a marker for activated macrophages, in numbers commensurate with those expressing LIF mRNA. LIF mRNA was also localized in surviving ORNs, identified by their expression of olfactory marker protein (OMP) mRNA and protein in near-adjacent sections. Our data suggest that LIF functions as a mitogen originating from recruited macrophages through an intercellular signaling pathway that stimulates proliferation of progenitor cells leading to neurogenesis and regeneration, and as an intracellular survival factor for traumatized ORNs.
Getchell
Thomas V
TV
Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0230, USA. tgetche@pop.uky.edu
Shah
Dharmen S
DS
Partin
James V
JV
Subhedar
Nishikant K
NK
Getchell
Marilyn L
ML
D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism; D019771:Axotomy; D002465:Cell Movement / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006131:Growth Inhibitors / Q000235:genetics*; D007150:Immunohistochemistry; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000235:genetics*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000235:genetics*; D009830:Olfactory Bulb / Q000293:injuries / Q000601:surgery; D009831:Olfactory Mucosa / Q000166:cytology / Q000378:metabolism; D018034:Olfactory Receptor Neurons / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics; D053606:Receptors, OSM-LIF; D012183:Retrograde Degeneration / Q000378:metabolism* / Q000503:physiopathology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008222:Lymphokines; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C036763:monocyte-macrophage differentiation antigen; D019938:Cyclin D1