Effects of prolactin on TSC2-null Eker rat cells and in pulmonary lymphangioleiomyomatosis.
BACKGROUND
Lymphangioleiomyomatosis, a cystic lung disease of women, is characterized by proliferation of smooth muscle-like lymphangioleiomyomatosis cells, which possess mutations in the tuberous sclerosis complex genes, TSC1/TSC2. Growth factors involved in lymphangioleiomyomatosis cell proliferation are unknown. Prolactin, an important reproductive hormone in women, is known to promote cell proliferation and survival in other tissues.


OBJECTIVE
To determine the role of prolactin in signaling and proliferation in lymphangioleiomyomatosis.


METHODS
Prolactin levels in the sera of patients with lymphangioleiomyomatosis were correlated with clinical status. Components of prolactin signal transduction pathways were assessed in lymphangioleiomyomatosis lesions from human lung explants by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Prolactin effects on proliferation and signaling were quantified in tuberin-deficient and tuberin-expressing rat cells in vitro.


RESULTS
Higher prolactin levels in the sera of patients with lymphangioleiomyomatosis were associated with a faster rate of decline in FEV(1) and an increased history of pneumothorax (P < 0.01). Higher levels of prolactin and prolactin receptor mRNA and immunoreactivity were found in lymphangioleiomyomatosis lesions when compared with vascular smooth muscle cells in the same region of tissue. This was accompanied by evidence of activation of signal transducer and activator of transcription-1 (STAT1), STAT3, p44/42, and p38 mitogen-activated protein kinase. Tsc2(-/-) Eker rat embryonic fibroblasts expressed more prolactin receptor than did Tsc2(+/+) cells, and responded to prolactin with increased proliferation and activation of the same signaling pathways seen in vivo.


CONCLUSIONS
Prolactin may be an important growth factor in the pathogenesis of lymphangioleiomyomatosis.
Terasaki
Yasuhiro
Y
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1590, USA.
Yahiro
Kinnosuke
K
Pacheco-Rodriguez
Gustavo
G
Steagall
Wendy K
WK
Stylianou
Mario P
MP
Evans
Jilly F
JF
Walker
Ameae M
AM
Moss
Joel
J
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D049109:Cell Proliferation; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008171:Lung Diseases / Q000097:blood* / Q000150:complications; D018192:Lymphangioleiomyomatosis / Q000097:blood* / Q000150:complications / Q000473:pathology; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D011030:Pneumothorax / Q000150:complications / Q000378:metabolism; D011388:Prolactin / Q000097:blood*; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D000077005:Tuberous Sclerosis Complex 2 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000097:blood*
C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011388:Prolactin