Abstract
BackgroundType II activation of macrophages is known to support Th2 responses development; however, the role of Th2 cytokines (esp. IL-4) on type II activation is unknown. To assess whether the central Th2 cytokine IL-4 can alter type II activation of macrophages, we compared the ability of bone marrow-derived macrophages from wild type (WT) and IL-4Rα-deficient mice to be classically or type II-activated in vitro.ResultsWe found that although both WT and IL-4Rα-deficient macrophages could be classically activated by LPS or type II activated by immune complexes plus LPS, IL-4Rα-deficient macrophages consistently produced much higher levels of IL-12p40 and IL-10 than WT macrophages. Additionally, we discovered that type II macrophages from both strains were capable of producing IL-4; however, this IL-4 was not responsible for the reduced IL-12p40 and IL-10 levels produced by WT mice. Instead, we found that derivation culture conditions (GM-CSF plus IL-3 versus M-CSF) could explain the different responses of BALB/c and IL-4Rα−/− macrophages, and these cytokines shaped the ensuing macrophage such that GM-CSF plus IL-3 promoted more IL-12 and IL-4 while M-CSF led to higher IL-10 production. Finally, we found that enhanced IL-4 production is characteristic of the type II activation state as other type II-activating products showed similar results.ConclusionsTaken together, these results implicate type II activated macrophages as an important innate immune source of IL-4 that may play an important role in shaping adaptive immune responses.
Highlights
Macrophages can become activated by a variety of different products and signals [1]
Because type II-activated macrophages have been shown to promote Th2 responses in vitro and in vivo, we investigated the role of the key Th2 cytokine, IL-4, in classical and type II activation
We found that both wild type (WT) and IL-4Ra2/2 BMMQ were able to become classically or type II-activated as shown by the IL-12 and IL-10 cytokine profiles (Figure 1)
Summary
One of the most commonly used macrophage activating products is lipopolysaccharide (LPS), the major outer membrane component of gram negative bacteria, and this microbial product classically activates macrophages into producing high levels of pro-inflammatory mediators such as IL12, TNF-a, and IL-6 [2] and enhance the expression of CD40, PD-L1, CD86, and iNOS [3,4] This phenotype can promote the differentiation of naıve CD4 T cells into Th1 cells and has been shown to be protective during microbial infections and detrimental during specific inflammatory disease models such as EAE [1]. The expression of CD40 and PD-L1 are significantly reduced, type IIactivated macrophages are effective antigen-presenting cells and promote the development of Th2 cells both in vitro and in vivo [3,7,8] This activation state can impair anti-microbial effector functions but has been shown to protect against pathology in proinflammatory disease models such as EAE and septic shock. To assess whether the central Th2 cytokine IL-4 can alter type II activation of macrophages, we compared the ability of bone marrow-derived macrophages from wild type (WT) and IL-4Radeficient mice to be classically or type II-activated in vitro
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