Microglial cells are the major phagocytic cells in the central nervous system (CNS), and accumulate at the sites of inflammatory responses in neurodegenerative diseases. When activated by pro-inflammatory stimulants, such as tumor necrosis factor alpha (TNFalpha), mouse microglial cells express a chemoattractant receptor formyl peptide receptor 2 (FPR2) which mediates cell migration in response to FPR2 specific agonists including amyloid beta (Abeta42), a pathogenic agent in Alzheimer´s disease. The present study investigates the capacity of IL-4, a Th2 type cytokine, to regulate microglial responses to TNFalpha. We found that TNFalpha-induced expression and function of FPR2 in microglial cells were markedly inhibited by IL-4. Mechanistic studies revealed that IL-4 attenuates TNFalpha-induced activation of ERK and p38 MAPK as well as NFkappaB in microglial cells, and the effect of IL-4 was independent of Stat6 activation. Since IL-4 is produced by astroglia in the CNS, our results suggest that IL-4 may play an important role in the maintenance of CNS homeostasis and in limiting inflammatory diseases.
