Exp Neurol. 2013 Aug 30. pii: S0014-4886(13)00247-1. doi: 10.1016/j.expneurol.2013.08.007. [Epub ahead of print]
The absence of indoleamine 2,3-dioxygenase expression protects against NMDA receptor-mediated excitotoxicity in mouse brain.
Mazarei G, Budac DP, Lu G, Lee H, Möller T, Leavitt BR.
Centre for Molecular Medicine and Therapeutics and Department of Medical Genetics, University of British Columbia, 980 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
We previously showed that the expression and activity of indoleamine 2,3-dioxygenase (Ido1) are chronically elevated in the striatum of YAC128 mouse model of HD. This was followed by increased production of neurotoxic metabolite hydroxykynurenine (3-HK) in the striatum of symptomatic mice. We therefore hypothesized that the chronic Ido1 induction in the striatum of YAC128 mice leads to increased neurotoxicity in this mouse model; based on this hypothesis, we predicted that the absence of Ido1 expression would result in decreased sensitivity to neurotoxicity in mice. The work described in this brief communication will include the characterization of Ido-/- striatum in terms of enzymatic expression and activity in the first step of the pathway. Additionally, we assessed the sensitivity of the striatum to excitotoxic insult in the absence of Ido1 expression in the striatum of constitutive Ido1 null mice (Ido-/-) and demonstrated that Ido-/- mice are less sensitive to QA-induced striatal neurotoxicity. Finally, through measurement of kynurenine pathway (KP) metabolites in Ido-/- mice, we showed decreased levels of 3-HK in the striatum of these mice. This study suggests that the inhibition of the first step in the KP may be neuroprotective and should be considered as a potential therapeutic target in HD and other neurodegenerative diseases.
Int Immunopharmacol. 2013 Sep 9. pii: S1567-5769(13)00339-1. doi: 10.1016/j.intimp.2013.08.018. [Epub ahead of print]
The tryptophan metabolite 3-hydroxyanthranilic acid suppresses T cell responses by inhibiting dendritic cell activation.
Lee WS, Lee SM, Kim MK, Park SG, Choi IW, Choi I, Joo YD, Park SJ, Kang SW, Seo SK.
Department of Hemato/Oncology, Busan Paik Hospital, College of Medicine, Inje University, Busan 614-735, South Korea.
The generation of tryptophan (Trp) metabolites by indoleamine 2,3-dioxygenase (IDO) is an effective mechanism for T cell suppression. However, the effect of Trp metabolites on dendritic cells (DCs) remains unclear. Here, we investigated whether the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) directly inhibits DC activation and is responsible for T cell suppression. We found that 3-HAA treatment significantly reduced IL-12, IL-6, and TNF-a production in bone marrow-derived DCs (BMDCs) stimulated with LPS. Maturation markers CD40, CD80, CD86, and I-A were also significantly reduced. Moreover, treatment with 3-HAA decreased the ability of DCs to stimulate T cell activation and differentiation in vitro and in vivo. Finally, we observed that phospho-JNK and phospho-38 levels were reduced in 3-HAA-treated DC2.4 cells and BMDCs. These results suggest that the tryptophan metabolite 3-HAA suppresses T cell responses by inhibiting DC activation.
Ann Rheum Dis. 2013 Sep 6. doi: 10.1136/annrheumdis-2013-203756. [Epub ahead of print]
The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells.
Kubo S, Yamaoka K, Kondo M, Yamagata K, Zhao J, Iwata S, Tanaka Y.
The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
OBJECTIVE:
Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib.
METHODS:
The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells.
RESULTS:
Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1ß production without affecting transforming growth factor (TGF)-ß and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2.
CONCLUSIONS:
Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs. |
