Recombinant TB10.4 of Mycobacterium bovis induces cytokine production in RAW264.7 macrophages through activation of the MAPK and NF-κB pathways via TLR2

Liu, Shuqing; Ji, Hong; Hou, Shaohua; Zhang, Gaimei; Xin, Ting; Li, Hegang; Yuan, Weifeng; Guo, Xiaoyu; Gao, Xintao; Li, Ming; Wu, Jing; Zhu, Hongfei

doi:10.1016/j.molimm.2014.06.026

Cited by 17 publications

(19 citation statements)

References 37 publications

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“…NF-κB is the primary transcription factor activated by TLR signaling, which is the key for triggering and coordinating both innate and adaptive immune responses ( 14 ). Previous studies have shown that the phosphorylation of NF-κB can be mediated by TLR2 ( 27 ), and induction of the NF-κB signaling pathway was correlated with NF-κB p65 ( 53 ). Recent studies indicated that a shift from p50–p65 heterodimer to p50 homodimers in NF-κB may participate in resolving inflammation ( 14 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

TLR2−/− Mice Display Decreased Severity of Giardiasis via Enhanced Proinflammatory Cytokines Production Dependent on AKT Signal Pathway

Zhang

Gong

et al. 2017

Front. Immunol.

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Giardia infection is one of the most common causes of waterborne diarrheal disease in a wide array of mammalian hosts, including humans globally. Although numerous studies have indicated that adaptive immune responses are important for Giardia defense, however, whether the host innate immune system such as TLRs recognizes Giardia remains poorly understood. TLR2 plays a crucial role in pathogen recognition, innate immunity activation, and the eventual pathogen elimination. In this study, we investigated the role of TLR2 as a non-protective inflammatory response on controlling the severity of giardiasis. RT-PCR analysis suggested that TLR2 expression was increased in vitro. We demonstrated that Giardia lamblia-induced cytokines expression by the activation of p38 and ERK pathways via TLR2. Interestingly, the expression of IL-12 p40, TNF-α, and IL-6, but not IFN-γ, was enhanced in TLR2-blocked and TLR2−/− mouse macrophages exposed to G. lamblia trophozoites compared with wild-type (WT) mouse macrophages. Further analysis demonstrated that G. lamblia trophozoites reduced cytokines secretion by activating AKT pathway in WT mouse macrophages. Immunohistochemical staining in G. lamblia cysts infected TLR2−/− and WT mice showed that TLR2 was highly expressed in duodenum in infected WT mice. Also, infected TLR2−/− and AKT-blocked mice showed an increased production of IL-12 p40 and IFN-γ compared with infected WT mice at the early stage during infection. Interestingly, infected TLR2−/− and AKT-blocked mice displayed a decreased parasite burden, an increased weight gain rate, and short parasite persistence. Histological morphometry showed shortened villus length, hyperplastic crypt and decreased ratio of villus height/crypt depth in infected WT mice compared with in infected TLR2−/− and AKT-blocked mice. Together, our results suggested that TLR2 deficiency leads to alleviation of giardiasis and reduction of parasite burden through the promotion of proinflammatory cytokines production. For the first time, our results demonstrated that TLR2 played a negative role in host defense against Giardia.

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Section: Discussionmentioning

confidence: 99%

TLR2−/− Mice Display Decreased Severity of Giardiasis via Enhanced Proinflammatory Cytokines Production Dependent on AKT Signal Pathway

Zhang

Gong

et al. 2017

Front. Immunol.

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“…by diverse stimuli to mediate intracellular signaling and are associated with a variety of cellular activities [38] . It has been reported that the MAPKs signal pathway is related to the LPSinduced expression of COX-2 and iNOS [39,40] . In this study, AA13 reduced the LPS-induced phosphorylation of p38 and JNK, but had no effect on the phosphorylation of ERK, though we did find that AA13 reduced the phosphorylation of ERK induced by hydrogen peroxide in SHSY5Y cells.…”

Section: Discussionmentioning

confidence: 99%

Sarsasapogenin-AA13 inhibits LPS-induced inflammatory responses in macrophage cells in vitro and relieves dimethylbenzene-induced ear edema in mice

et al. 2017

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Sarsasapogenin-AA13 (AA13) is a novel synthetic derivative of sarsasapogenin extracted from the Chinese herb Rhizoma Anemarrhenae. In this study we investigated the effects of AA13 on lipopolysaccharide (LPS)-induced production of inflammatory factors in macrophage cells and the anti-inflammatory activity of AA13 in an inflammatory model of dimethylbenzene-induced ear edema. Macrophage cells (RAW264.7 cells and mouse peritoneal macrophages) were exposed to LPS (1 μg/mL); pretreatment with AA13 (5-20 μmol/L) dose-dependently inhibited LPS-induced production of NO, TNF-α and PGE, and LPS-stimulated expression levels of COX-2 and iNOS. Furthermore, pretreatment with AA13 dose-dependently suppressed LPS-stimulated phosphorylation of p38 and JNK, but had no effect on ERK in RAW264.7 cells. Moreover, pretreatment with AA13 inhibited LPS-induced activation of the nuclear factor (NF)-κB in RAW264.7 cells. The in vivo anti-inflammatory activity of AA13 was demonstrated in a mouse inflammatory model: pre-treatment with either AA13 (20 mg·kg·d, ig) or a positive control antifani (10 mg·kg·d, ig) for 3 d significantly relieved dimethylbenzene-induced ear edema. Our results demonstrate that AA13 effectively inhibit LPS-induced inflammatory responses in macrophage cells in vitro and relieve dimethylbenzene-induced ear edema in vivo.

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“…Furthermore, an Rv1411/ESAT-6 fusion protein has been shown to enhance vaccine efficacy in the absence of additional Th1 response-inducing adjuvants, indicating that this protein has natural adjuvanticity due to its interaction with TLR2 [ 32 , 38 , 39 ]. Alternatively, the Mtb Ag TB10.4, which is a TLR2 agonist, induces a strong Th1 response mediated by CD4 + T cells and displays good vaccine potential [ 40 ], and ESAT-6, the most fully characterized immunogenic Mtb Ag, promotes protective Th1 and Th17 responses in a TLR2-dependent manner [ 31 ]. These two Ags (TB10.4 and ESAT-6) are secreted during the infection course, and their common features are recognized by the host immune system [ 31 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, the Mtb Ag TB10.4, which is a TLR2 agonist, induces a strong Th1 response mediated by CD4 + T cells and displays good vaccine potential [ 40 ], and ESAT-6, the most fully characterized immunogenic Mtb Ag, promotes protective Th1 and Th17 responses in a TLR2-dependent manner [ 31 ]. These two Ags (TB10.4 and ESAT-6) are secreted during the infection course, and their common features are recognized by the host immune system [ 31 , 40 ]. Thus, gaining an understanding of the cross-talk that forms between TLR2 and Mtb Ags will impact the design of novel therapeutic strategies and the development of vaccines and immunotherapy regimens.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Rv3628 drives Th1-type T cell immunity via TLR2-mediated activation of dendritic cells and displays vaccine potential against the hyper-virulent Beijing K strain

Kim

Bin

et al. 2016

Oncotarget

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Identification of vaccine target antigens (Ags) that induce Ag-specific Th1 immunity is the first step toward the development of a tuberculosis vaccine. Here, we evaluated the Mycobacterium tuberculosis (Mtb) protein Rv3628, a soluble inorganic pyrophosphatase, as a vaccine target and characterized the molecular details of its interaction with dendritic cells (DCs). Rv3628 activated DCs, increasing their expression of cell surface molecules and augmenting their production of TNF-α, IL-1β, IL-6, and IL-12p70. Rv3628 mediated these effects by binding to TLR2 and activating downstream MyD88-, MAPK- and NF-κB-dependent signaling pathways. Rv3628-stimulated DCs induced the expansion of OVA-specific CD4+ and CD8+ T cells, which secreted IFN-γ and IL-2. Rv3628-specific effector/memory T cells expanded to a similar extent as those stimulated with ESAT-6 Ag in samples of lung and spleen cells collected from Mtb-infected mice. Finally, an Rv3628 subunit vaccine adjuvanted with dimethyldioctadecylammonium liposomes containing monophosphoryl lipid-A caused significant reductions in bacterial counts and lung inflammation after challenge with the hyper-virulent Mtb K strain. Importantly, protective efficacy was correlated with the generation of Rv3628-specific CD4+ T cells co-producing IFN-γ, TNF-α and IL-2 and exhibiting an elevated IFN-γ recall response. Thus, Rv3628 polarizes DCs toward a Th1 phenotype and promotes protective immunity against Mtb infection.

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Recombinant TB10.4 of Mycobacterium bovis induces cytokine production in RAW264.7 macrophages through activation of the MAPK and NF-κB pathways via TLR2

Cited by 17 publications

References 37 publications

TLR2−/− Mice Display Decreased Severity of Giardiasis via Enhanced Proinflammatory Cytokines Production Dependent on AKT Signal Pathway

TLR2−/− Mice Display Decreased Severity of Giardiasis via Enhanced Proinflammatory Cytokines Production Dependent on AKT Signal Pathway

Sarsasapogenin-AA13 inhibits LPS-induced inflammatory responses in macrophage cells in vitro and relieves dimethylbenzene-induced ear edema in mice

Mycobacterium tuberculosis Rv3628 drives Th1-type T cell immunity via TLR2-mediated activation of dendritic cells and displays vaccine potential against the hyper-virulent Beijing K strain

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