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IL-21 Modulates Release of Proinflammatory Cytokines in LPS-Stimulated Macrophages through Distinct Signaling Pathways

DOI: 10.1155/2013/548073

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The aim of this study was to investigate the anti-inflammatory effect of IL-21 on LPS-induced mouse peritoneal macrophages. The results showed that IL-21 significantly inhibited LPS-induced mRNA expression of IL-1β, TNF-α, and IL-6 in macrophages, but not of IFN-γ, IL-10, CCL5, or CXCL2. ELISA analysis showed that IL-21 also suppressed LPS-induced production of TNF-α and IL-6 in culture supernatants. Western blot analysis showed that IL-21 clearly inhibited ERK and IκBα phosphorylation and NF-κB translocation in LPS-stimulated macrophages, but it increased STAT3 phosphorylation. Flow cytometric and Western blot analysis showed that IL-21 decreased M1 macrophages surface markers expression of CD86, iNOS, and TLR4 in LPS-stimulated cells. All results suggested that IL-21 decreases IL-6 and TNF-α production via inhibiting the phosphorylation of ERK and translocation of NF-κB and promotes a shift from the M1 to M2 macrophage phenotype by decreasing the expression of CD86, iNOS, and TLR4 and by increasing STAT3 phosphorylation in LPS-stimulated cells. 1. Introduction Interleukin-21 (IL-21) is produced by activated CD4+ T-cells, natural killer T cells (NKT cells), and follicular T helper cells. The IL-21 receptor was discovered in 2000 as an orphan receptor, first denoted as NILR for novel interleukin receptor and now as IL-21R [1, 2]. IL-21 receptor expression has been detected on CD4+ T cells, CD8+ T cells, B cells, NK cells, macrophages, and dendritic cells (DCs) [1–6], suggesting that IL-21 has a broad range of functions. In addition, the IL-21 receptor is a member of a family of receptors that share the γ chain (γc). Analogous to the other γc family cytokines, IL-21 activates both Jak1 and Jak3 [1, 7, 8], and weakly activates Stat5 proteins [9]. Stat3 appears to be the most important STAT protein for IL-21 signaling. In addition, the phosphoinositol 3-kinase/Akt (PI3K/Akt) and Ras/MAP kinase (MAPK) pathways also contribute to IL-21 signaling [10]. IL-21 also clearly has an important effect on B cells, T cells, and NK T cells. For example, IL-21 can augment anti-CD40-induced human B-cell proliferation, but it inhibits proliferation to anti-IgM and IL-4 [2] and can increase the proliferation of NK T cells in response to in vitro stimulation with anti-CD3, but only when combined with either IL-2 or IL-15 [11]. Macrophages are important innate immune cells that are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells, and debris and recruit additional macrophages in response to inflammatory signals.


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