Abstract
Lactobacillus helveticus SBT2171 (LH2171) has been reported to ameliorate the development of autoimmune diseases, such as collagen-induced arthritis and experimental autoimmune encephalitis in mice and inhibit interleukin (IL)-6 production in antigen-presenting cells in vitro. Regulation of cytokine production by antigen-presenting cells might be critical for the anti-inflammatory function of LH2171 in autoimmune diseases. However, the mechanism and contributing components of LH2171-mediated inhibition of IL-6 production are unclear. Here, we examined the anti-inflammatory effects of LH2171 in lipopolysaccharide (LPS)-stimulated peritoneal macrophages, as a model of antigen-presenting cells, necessary for the pathogenesis of autoimmune diseases. LH2171 significantly reduced LPS-induced expression and secretion of IL-6 and IL-1β cytokines. It also inhibited activation of nuclear factor-kappa B and mitogen-activated protein kinases (NF-κB/MAPKs). Moreover, LH2171 induced gene expression of several negative regulators of NF-κB/MAPKs. Among these regulators, A20 was strongly up-regulated at the mRNA and protein levels upon LH2171 treatment. The cell wall fraction of LH2171 also demonstrated a similar increase in A20 gene expression and exerted an anti-inflammatory effect. These results suggest that the cell wall may be one of the anti-inflammatory components of LH2171. Since cell wall components of Gram-positive bacteria are recognized by toll-like receptor 2 (TLR2), we investigated whether the anti-inflammatory effect of LH2171 was mediated by TLR2 signaling. Specifically, LH2171-mediated IL-6 suppression and A20 upregulation in wild-type macrophages were reversed and significantly reduced in TLR2 knock-out macrophages. These results suggest that LH2171 induces A20 expression via TLR2 signaling, inhibiting the activation of NF-κB/MAPKs and cytokine production in antigen-presenting cells. This might contribute to the anti-inflammatory activity of LH2171 on autoimmune diseases.
Highlights
Regulation of immune responses is important for the prevention of many diseases
The increase in A20 mRNA expression induced by L. helveticus SBT2171 (LH2171) treatment was significantly weaker in peritoneal macrophages of toll-like receptor 2 (TLR2) KO mice than wild-type mice (Figure 6C). These results indicated that LH2171 induction of A20 expression and suppression of IL-6 secretion in peritoneal macrophages are mediated by TLR2 signaling
Earlier studies have reported that intraperitoneal injection of LH2171 improved clinical symptoms and decreased serum IL6 level in mice with collagen-induced arthritis (CIA) [18, 19]
Summary
Regulation of immune responses is important for the prevention of many diseases. Activation of an immune response is required to eliminate virus-infected cells or cancer cells, whereas an excessive inflammatory response may result in the onset of a physiological disorder or even death. Excessive inflammation is caused by stimulation of pathogen-associated molecular patterns (PAMPs) via toll-like receptors (TLRs) [1]. LPS activates inflammatory signaling pathways, which are mediated by molecules, such as nuclear factor-kappa B (NF-κB) and mitogenactivated protein kinases (MAPKs) [2]. In the last two decades, it has been proven that TLR signaling could be activated by PAMPs and damage-associated molecular patterns (DAMPs), which are endogenous danger signals produced by injured or dead cells [3,4,5]. Recent studies indicate that activation of TLR signaling pathways by PAMPs or DAMPs has an essential role in the pathogenesis and development of inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis [6,7,8,9]. It was reported that the severity of murine collagen-induced arthritis (CIA), a model of human rheumatoid arthritis, was suppressed upon administration of a TLR4 antagonist [10]
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