1. Academic Validation
  2. Autocrine secretion of insulin-like growth factor-I mediates growth hormone-stimulated DNA synthesis and proliferation in primary cultures of adult rat hepatocytes

Autocrine secretion of insulin-like growth factor-I mediates growth hormone-stimulated DNA synthesis and proliferation in primary cultures of adult rat hepatocytes

  • Eur J Pharmacol. 2021 Jan 15;891:173753. doi: 10.1016/j.ejphar.2020.173753.
Kazuki Kurihara 1 Hajime Moteki 1 Mitsutoshi Kimura 1 Masahiko Ogihara 2
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, School of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado City, Saitama, 350-0295, Japan.
  • 2 Department of Clinical Pharmacology, School of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado City, Saitama, 350-0295, Japan. Electronic address: ogiharam@josai.ac.jp.
Abstract

The intracellular signaling pathway of growth hormone (GH)-stimulated DNA synthesis and proliferation was investigated in primary cultures of adult rat hepatocytes. DNA synthesis and cell proliferation were detected in hepatocyte parenchymal cells grown in serum-free, defined medium containing GH (100 ng/ml). GH-stimulated hepatocyte DNA synthesis and proliferation were almost completely blocked by TG101209 (10-6 M), a selective Janus kinase (JAK)2 inhibitor, U-73122 (10-6 M), a selective Phospholipase C (PLC) inhibitor, and a monoclonal antibody to insulin-like growth factor-I (IGF-I) receptor (100 ng/ml) or anti-secretion agents such as somatostatin (10-6 M) and BAPTA/AM (10-7 M). In addition, blocking monoclonal Antibodies to IGF-I, but not transforming growth factor-α, completely inhibited GH-induced hepatocyte DNA synthesis and proliferation. IGF-I levels in the culture medium increased rapidly versus baseline levels within 5 min in response to GH (100 ng/ml), and the maximum IGF-I level (100 pg/ml) was reached 20 min after GH stimulation. Autocrine secretion of IGF-I into the culture medium was inhibited by a growth-inhibitory dose of TG101209, U-73122, somatostatin, or BAPTA/AM. These data indicate that the proliferative mechanism of action of GH is mediated mainly through a GH receptor/JAK2/PLC-stimulated increase in the autocrine secretion of IGF-I by primary cultured hepatocytes, followed by stimulation of the 95 kDa IGF-I receptor tyrosine kinase signaling pathway.

Keywords

Autocrine secretion; Growth hormone (GH); Hepatocyte proliferation (cultured hepatocytes); Insulin-like growth factor (IGF)-I.

Figures
Products