IL-4 inhibits the expression of mouse formyl peptide receptor 2, a receptor for amyloid beta1-42, in TNF-alpha-activated microglia.
Microglia are phagocytic cells in the CNS and actively participate in proinflammatory responses in neurodegenerative diseases. We have previously shown that TNF-alpha up-regulated the expression of formyl peptide receptor 2 (mFPR2) in mouse microglial cells, resulting in increased chemotactic responses of such cells to mFPR2 agonists, including amyloid beta1-42 (Abeta42), a critical pathogenic agent in Alzheimer's disease. In the present study, we found that IL-4, a Th2-type cytokine, markedly inhibited TNF-alpha-induced expression of mFPR2 in microglial cells by attenuating activation of ERK and p38 MAPK as well as NF-kappaB. The effect of IL-4 was not dependent on Stat6 but rather required the protein phosphatase 2A (PP2A) as demonstrated by the capacity of PP2A small interfering RNA to reverse the effect of IL-4 in TNF-alpha-activated microglia. Since both IL-4 and TNF-alpha are produced in the CNS under pathophysiological conditions, our results suggest that IL-4 may play an important role in the maintenance of CNS homeostasis by limiting microglial activation by proinflammatory stimulants.
Iribarren
Pablo
P
Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, MD 21702, USA.
Chen
Keqiang
K
Hu
Jinyue
J
Zhang
Xia
X
Gong
Wanghua
W
Wang
Ji Ming
JM
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002633:Chemotaxis / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D054648:Protein Phosphatase 2; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors* / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D050800:STAT6 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); C481578:formyl peptide receptor 2, mouse; D015847:Interleukin-4; D048049:Extracellular Signal-Regulated MAP Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2