Abstract
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.
Highlights
Interleukin-21 (IL-21) is produced by activated CD4+ T-cells, natural killer T cells (NKT cells), and follicular T helper cells
The results showed that IL-21 triggers the activation of ERK1/2 in 20 min, and LPS stimulation significantly increased the phosphorylation of ERK1/2, p38 MAP kinase (MAPK), and Jun N-terminal kinase (JNK) at 5, 20, and 60 min, respectively
Biologic activities of IL-21 are mediated by a specific IL-21R, structurally related to the IL-21R chain, which is associated with the common γc for signal transduction [22, 23]
Summary
Interleukin-21 (IL-21) is produced by activated CD4+ T-cells, natural killer T cells (NKT cells), and follicular T helper cells. 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. LPS activates NF-κB and the MAPK family, which are classified into at least three components: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), and p38 MAPK, which have been implicated in the release of immune-related cytotoxic factors such as inducible NO synthase (iNOS), cyclooxygenase (COX)-2, and proinflammatory cytokines such as TNFα, IL-1β, and IL-6 [12,13,14]. We studied the mRNA expression and protein secretion of cytokines and chemokines and the activity of two signal pathways, MAPKs and NF-κB, which are activated by TLR4 and responsible for the regulation of the intracellular secretion of proinflammatory cytokine. We studied the expression of M1 macrophage surface markers such as CD86, iNOS, and TLR4 and the phosphorylation of STAT3 to confirm whether IL-21 can affect population of M1 macrophages in LPS-stimulated cells
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