Boosting Interleukin-10 Production: Therapeutic Effects and Mechanisms

Raveney

The American Journal of Pathology

et al. 2009

Recent evidence suggests that interleukin-17-producing CD4؉ T cells (Th17 cells) are the dominant pathogenic cellular component in autoimmune inflammatory diseases, including multiple sclerosis. It has recently been demonstrated that all-trans retinoic acid can suppress Th17 differentiation and promote the generation of Foxp3 ؉ regulatory T cells via retinoic acid receptor signals. Here, we investigated the effects of AM80, a synthetic retinoid with enhanced biological properties to all-trans retinoic acid, on Th17 differentiation and function and evaluated its therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. AM80 treatment was more effective than all-trans retinoic acid in inhibiting Th17 differentiation in vitro. Oral administration of AM80 was protective for the early development of EAE and the down-modulation of Th17 differentiation and effector functions in vivo. Moreover, AM80 inhibited interleukin-17 production by splenic memory T cells, in vitro-differentiated Th17 cells, and central nervous system-infiltrating effector T cells. Accordingly, AM80 was effective when administered therapeutically after the onset of EAE. Continuous AM80 treatment, however, was ineffective at inhibiting late EAE symptoms despite the maintained suppression of ROR␥t and interleukin-17 expression levels by central nervous system-infiltrating T cells. We reveal that continuous AM80 treatment also led to the suppression of interleukin-10 production by a distinct T cell subset that expressed both Foxp3 and ROR␥t. These findings suggest that retinoid signaling regulates both inflammatory Th17 cells and Th17-like regulatory cells. (Am J Pathol

Section: Continuous Treatment With Rar Agonists Abrogate Il-10 Producsupporting

confidence: 68%

Synthetic Retinoid AM80 Inhibits Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis

Raveney

The American Journal of Pathology

et al. 2009

Korean J Physiol Pharmacol

“…In addition to sepsis, IL-10 has been reported to be beneficial in various other inflammatory diseases, including inflammatory bowel disorders, multiple sclerosis and rheumatoid arthritis (Pestka et al, 2004). Boosting endogenous IL-10 production has been suggested as an important strategy for treating various inflammatory disorders (Zhou et al 2005). Thus, the IL-10 elevating activity of decursinol could be potentially effective in these disorders.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Decursinol on Mouse Models of Sepsis: Enhancement of Interleukin-10

Jung

Yan

Song

2008

The effects of decursinol on various models of sepsis were investigated. Intra-peritoneal pretreatment of mice with various doses of decursinol (1∼ 100 mg/kg) effectively suppressed lethality induced in three mouse models of experimental sepsis, i.e., lipopolysaccharide (LPS)/D-galactosamine (GalN), high-dose LPS (20 mg/kg), and cecal ligation and puncture (CLP). Intra-peritoneal pretreatment of mice with decursinol (50 mg/kg) markedly enhanced the LPS/GalN-induced increase of plasma interleukin-10 (IL-10) levels, without affecting plasma TNF-α , IL-6 and IL-12 levels. These results suggest that decursinol could be effective for prevention or treatment of sepsis.

The Journal of Immunology

“…The secretion of the anti-inflammatory cytokine IL-10 was also significantly increased in mice receiving ␣GalCerMPEG. In this context, there are currently attempts to develop agents able to promote endogenous IL-10 production for the treatment of allergies and inflammatory diseases (54,55). This suggests that ␣GalCerMPEG might also found an application for the development of immune therapies in this field.…”

Section: Discussionmentioning

confidence: 99%

A Pegylated Derivative of α-Galactosylceramide Exhibits Improved Biological Properties

Ebensen

Link

Riese

et al. 2007

The glycolipid α-galactosylceramide (αGalCer) has immunomodulatory properties, which have been exploited to combat cancer, chronic inflammatory diseases, and infections. However, its poor solubility makes αGalCer a suboptimal compound for in vivo applications. In this study, a pegylated derivative of αGalCer is characterized, which exhibits improved physical and biological properties. The new compound, αGalCerMPEG, is water-soluble and retains the specificity for the CD1d receptor of αGalCer. The in vitro stimulatory properties on immune cells (e.g., dendritic cells and splenocytes) are maintained intact, even when tested at a 33-fold lower concentration of the active moiety than αGalCer. NK cells isolated from mice treated with αGalCerMPEG also had stronger cytotoxic activity on YAC-1 cells than those obtained from animals receiving either αGalCer or CpG. Intranasal immunization studies performed in mice showed that αGalCerMPEG exerts stronger adjuvant activities than the parental compound αGalCer when tested at 0.35 vs 11.7 nM/dose. Coadministration of β-galactosidase with αGalCerMPEG resulted not only in high titers of Ag-specific Abs in serum (i.e., 1:512,000), but also in the stimulation of stronger Th2 and secretory IgA responses, both at local and remote mucosal effector sites (i.e., nose, lung, and vagina). The new synthetic derivative αGalCerMPEG represents a promising tool for the development of immune interventions against infectious and noninfectious diseases.