Effects of Prolactin on TSC2-null Eker Rat Cells and in Pulmonary Lymphangioleiomyomatosis (LAM)

Terasaki Y, Yahiro K, Pacheco-Rodriguez G, Steagall WK, Stylianou MP, Evans JF, Walker AM, Moss J.

Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States.

Abstract

Rationale

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 LAM 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 on signaling and proliferation in lymphangioleiomyomatosis.

Methods

Prolactin levels in lymphangioleiomyomatosis patient sera were correlated with clinical status. Components of prolactin signal transduction pathways were assessed in lymphangioleiomyomatosis lesions from human lung explants by real time RT-PCR and immunohistochemistry. Prolactin effects on proliferation and signaling were quantified in tuberin-deficient and tuberin-expressing rat cells in vitro.

Measurements and Main Results

Higher prolactin levels in sera of lymphangioleiomyomatosis patients were associated with a faster rate of decline in FEV1 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 STAT1, STAT3, p44/42, and p38 MAPK. 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.

PMID: 20413627 [PubMed - as supplied by publisher]