IL-10 synergistically enhances GM-CSF-induced CCR1 expression in myelomonocytic cells

Biochem Biophys Res Commun. 2003 May 2;304(2):417-24. doi: 10.1016/s0006-291x(03)00612-0.

Abstract

CC chemokine receptor 1 (CCR1) has been implicated in inflammation. The present study examined the signaling mechanisms that mediate GM-CSF/IL-10-induced synergistic CCR1 protein expression in monocytic U937 cells. GM-CSF alone markedly increased both the mRNA and protein expression of CCR1. IL-10 augmented GM-CSF-induced CCR1 protein expression with no effect on mRNA expression. PD098059 and U0126 (two MEK inhibitors), and LY294002 (a PI3K inhibitor) inhibited GM-CSF/IL-10-induced CCR1 gene and protein expression. PD098059, U0126, and LY294002 also attenuated chemotaxis of GM-CSF/IL-10-primed U937 cells in response to MIP-1alpha. Immunoblotting studies show that GM-CSF alone induced ERK2 phosphorylation; whereas, IL-10 alone induced p70(S6k) phosphorylation in U937 cells. Neither cytokine when used alone induced PKB/Akt phosphorylation. Combined GM-CSF/IL-10 treatment of U937 cells induced phosphorylation of ERK2, p70(S6k), and PKB/Akt. PD098059 and U0126 completely abrogated ERK2 phosphorylation; whereas, LY294002 completely blocked PKB/Akt and p70(S6k) phosphorylation. Our findings indicate that IL-10 may potentiate GM-CSF-induced CCR1 protein expression in U937 cells via activation of PKB/Akt and p70(S6k).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemokine CCL3
  • Chemokine CCL4
  • Chemotaxis, Leukocyte
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • Humans
  • Interleukin-10 / pharmacology*
  • Macrophage Inflammatory Proteins / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology
  • Phosphorylation
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / biosynthesis
  • Receptors, CCR1
  • Receptors, Chemokine / biosynthesis*
  • Receptors, Chemokine / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / drug effects
  • U937 Cells

Substances

  • CCR1 protein, human
  • Chemokine CCL3
  • Chemokine CCL4
  • Enzyme Inhibitors
  • Macrophage Inflammatory Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, CCR1
  • Receptors, Chemokine
  • Interleukin-10
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Mitogen-Activated Protein Kinases