Insulin-like growth factor I promotes maturation and inhibits apoptosis of immature cord blood monocyte-derived dendritic cells through MEK and PI 3-kinase pathways

Pediatr Res. 2003 Dec;54(6):919-25. doi: 10.1203/01.PDR.0000088067.04673.1B. Epub 2003 Aug 20.

Abstract

IGF-I has profound effects on the immune system. We previously reported that IGF-I promoted cord blood (CB)-naïve T-cell maturation and now show that IGF-I promoted maturation of CB monocyte-derived dendritic cells (DC) with up-regulation of CD83, CD86, CD40, and major histocompatibility complex (MHC) class II molecules, and down-regulation of mannose receptor. Furthermore, IGF-I inhibited apoptosis of CB DC and increased the production of tumor necrosis factor alpha (TNF-alpha). These effects were blocked by specific mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059) and phosphoinositol 3-kinase inhibitor (LY294002). PD98059 partially inhibited the IGF-I-induced up-regulation of MHC class II. In contrast, LY294002 was additive in the IGF-I-induced up-regulation of MHC class II. Moreover, LY294002 significantly increased the percentage of late apoptotic cells in CB. These results imply the involvement of different pathways for the differential regulation of co-stimulatory molecule expression and apoptosis. The addition of anti-TNF-alpha did not neutralize the effects of IGF-I on CB DC maturation and apoptosis. On the contrary, neutralizing TNF-alpha significantly increased the IGF-I-induced up-regulation of CD83 and CD40. We conclude that IGF-I has maturation and survival effects on CB DC. These effects are mediated through both MEK and PI 3-kinase pathways but not through the IGF-I induction of TNF-alpha production by the DC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / immunology
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cell Division / drug effects
  • Cell Division / immunology
  • Chromones / pharmacology
  • Dendritic Cells / cytology*
  • Dendritic Cells / enzymology
  • Enzyme Inhibitors / pharmacology
  • Fetal Blood / cytology
  • Flavonoids / pharmacology
  • Humans
  • Infant, Newborn
  • Insulin-Like Growth Factor I / pharmacology*
  • Lymphocytes / cytology
  • MAP Kinase Kinase Kinase 1*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism*
  • Monocytes / cytology*
  • Monocytes / drug effects
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Chromones
  • Enzyme Inhibitors
  • Flavonoids
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Insulin-Like Growth Factor I
  • MAP Kinase Kinase Kinase 1
  • MAP Kinase Kinase Kinases
  • MAP3K1 protein, human
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one