T Cell Pathways Involving CTLA4 Contribute To a Model of Acute Lung Injury

Nakajima, Takeshi; Suarez, Carlos J.; Lin, Ko-Wei; Jen, Kai Yu; Schnitzer, Jan E.; Makani, Samir; Parker, Nathan J.; Perkins, David L.; Finn, Patricia W.

doi:10.4049/jimmunol.0903238

Cited by 54 publications

(43 citation statements)

References 34 publications

(31 reference statements)

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“…[40][41][42] Furthermore, airway smooth muscles present from the bronchial tree up to the terminal bronchioles are highly activated during inflammation and lung tissue damage with engagement of TLRs promoting nonspecific airway hyperresponsiveness. Therefore, LPS instillation provides a useful experimental system for investigating the mechanisms of AHR in anesthetized and ventilated mice.…”

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confidence: 99%

α-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

D'Almeida¹,

Oliveira²,

Souza³

et al. 2017

IJN

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Acute respiratory distress syndrome (ARDS) is a severe clinical condition of respiratory failure due to an intense inflammatory response with different etiologies. Despite all efforts, therapy remains limited, and ARDS is still associated with high mortality and morbidity. Plants can provide a vast source of active natural products for the discovery of new drugs. α-bisabolol (α-bis), a constituent of the essential oil from chamomile, has elicited pharmacological interest. However, the molecule has some limitations to its biological application. This study was conducted to develop a drug delivery system using lipid-core nanocapsules (LNCs) to improve the anti-inflammatory effects of orally administered α-bis. α-bis-loaded LNCs (α-bis-LNCs) were prepared by interfacial deposition of poly(ε-caprolactone) and orally administered in a mouse model of ARDS triggered by an intranasal administration of lipopolysaccharide (LPS). We found that α-bis-LNCs (30, 50, and 100 mg kg −1 ) significantly reduced airway hyperreactivity (AHR), neutrophil infiltration, myeloperoxidase activity, chemokine levels (KC and MIP-2), and tissue lung injury 18 hours after the LPS challenge. By contrast, free α-bis failed to modify AHR and neutrophil accumulation in the bronchoalveolar lavage effluent and lung parenchyma and inhibited elevation in the myeloperoxidase and MIP-2 levels only at the highest dose. Furthermore, only α-bis-LNCs reduced LPS-induced changes in mitogen-activated protein kinase signaling, as observed by a significant reduction in phosphorylation levels of ERK1/2, JNK, and p38 proteins. Taken together, our results clearly show that by using LNCs, α-bis was able to decrease LPS-induced inflammation. These findings may be explained by the robust increase of α-bis concentration in the lung tissue that was achieved by the LNCs. Altogether, these results indicate that α-bis-LNCs should further be investigated as a potential alternative for the treatment of ARDS.

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mentioning

confidence: 99%

α-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

D'Almeida¹,

Oliveira²,

Souza³

et al. 2017

IJN

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“…Lungs were harvested at 48 hours after LPS exposure. Bronchoalveolar lavage (BAL) fluid and BAL cells were collected as previously described (22). I-cAMP and anti-cAMP antibody.…”

Section: Acute Lung Injury Modelmentioning

confidence: 99%

“…We previously showed that CTLA4 expression is increased in an LPS-induced model of acute lung injury (ALI), then tested whether LPS modifies CTLA4 at the level of transcription (22). We analyzed LPS stimulation of the CTLA4 promoters at different time points.…”

Section: Rapamycin Decreases Lps-or Camp-induced Ctla4 Transcriptionmentioning

confidence: 99%

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Regulation of Cytotoxic T Lymphocyte Antigen 4 by Cyclic AMP

Lin

Murray

et al. 2013

Am J Respir Cell Mol Biol

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Recent studies indicate that cyclic AMP (cAMP) induces cytotoxic T lymphocyte antigen (CTLA) 4. CTLA4 is expressed in T cells, and is a negative regulator of T cell activation. CTLA4 expression is regulated by T cell receptor plus CD28 (adaptive immune signaling) at both the transcriptional and post-transcriptional level. Here, we examine the pathways by which cAMP regulates CTLA4 expression, focusing on transcriptional activation. Elevating intracellular cAMP levels by cellpermeable cAMP analogs, the adenylyl cyclase activator, forskolin, or phosphodiesterase inhibitors increases CTLA4 mRNA expression in EL4 murine T cells and primary CD41 T cells. Activation of protein kinase A (using the protein kinase A-selective agonist, N6-phenyladenosine-cAMP), but not exchange proteins activated by cAMP (using the exchange proteins activated by cAMP-selective 8-pCPT-2Me-cAMP), increases CTLA4 promoter activity. Mutation constructs of the CTLA4 promoter uncover an enhancer binding site located within the 2150 to 2130 bp region relative to the transcription start site. Promoter analysis and chromatin immunoprecipitation assays suggest that cAMP response element-binding is a putative transcription factor induced by cAMP. We have previously shown that CTLA4 mediates decreased pulmonary inflammation in an LPSinduced murine model of acute lung injury (ALI). We observed that LPS can induce CTLA4 transcription via the same cAMP-inducible promoter region. The immunosuppressant, rapamycin, decreases cAMP and LPS-induced CTLA4 transcription in vitro. In vivo, LPS induces cAMP accumulation in bronchoalveolar lavage fluid, bronchoalveolar lavage cells, and lung tissues in ALI. We demonstrate that rapamycin decreases cAMP accumulation and CTLA4 expression in ALI. Together, these data suggest that cAMP may negatively regulate pulmonary inflammatory responses in vivo and in vitro by altering CTLA4 expression.Keywords: cytotoxic T lymphocyte antigen 4; cAMP; acute lung injury; protein kinase A; rapamycin Activated T cells express negative regulators, including cytotoxic T lymphocyte antigen (CTLA) 4, a negative regulator of T cell activation (1-3). CTLA4 binds to CD80 or CD86 with greater affinity than CD28 to block costimulatory signals, leading to inhibition of cell cycle progression and IL-2 production (4). The blockade of CTLA4 by antibody prevents the accumulation of inducible cyclic AMP (cAMP) early repressor and cAMP response element modulator, and leads to the rescue of IL-2 expression (5, 6). cAMP has a similar inhibitory effect on proliferation and IL-2 production in T cells (7,8).cAMP is an important second messenger in many biological processes. cAMP is synthesized from ATP by adenylyl cyclase and degraded by phosphodiesterase (PDE). In physiological conditions, a wide range of signaling molecules, such as epinephrine, glucagon, and prostaglandin E2, increase cAMP accumulation via G protein-coupled receptor. cAMP can also be activated in response to microbial challenges or LPS (9). The main targets of cAMP are protein kinase ...

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“…Th17 cells play potent pro-inflammatory roles by secreting cytokine IL-17A, IL-22, IL-6, and TNF-α [15,19]. IL-17 potently induces the production of IL-8 and G-CSF from epithelial cells and fibroblasts, thereby resulting in neutrophil activation and recruitment.…”

Section: Introductionmentioning

confidence: 99%

KGF-2 ameliorates acute lung injury via inhibiting TH17 cells-NF-κB-dependent inflammation and activating the PI3K/Akt survival signaling pathway in mice

Wang¹,

Wang²,

Ji³

et al. 2018

Oncotarget

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Acute lung injury is characterized by alveolar injury, inflammation, and infiltration of inflammatory cells. Although the protective effects of keratinocyte growth factor-2 on ALI have been defined, the mechanisms remain unclear. Lipopolysaccharides (Pseudomonas aeruginosa) was administered intratracheally into mice lungs, and peak lung injury occurred on day 6 after the LPS challenge, with resolution on day 10. A progressive influx of CD4 + CD25 + Foxp3 + T cells into the lungs and spleen on day 1, which peaked on day 6, and was maintained at high level on day 10. The percentage of Th17 cells in lung tissue and blood was higher in the ALI group than in the control group, which peaked on day 2, and returned to nearly normal on day 10. KGF-2 attenuated lung injury by inhibiting the prevalence of Th17 cells through STAT3 dysfunction and NF-κB signal, and improved survival rate by activating the PI3K/Akt signal. These results illustrated a new mechanism of KGF-2 on ALI by inhibiting Th17 cells mediated by STAT3-NF-κB, and activating the PI3k/Akt signal.

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T Cell Pathways Involving CTLA4 Contribute To a Model of Acute Lung Injury

Cited by 54 publications

References 34 publications

α-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

α-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

Regulation of Cytotoxic T Lymphocyte Antigen 4 by Cyclic AMP

KGF-2 ameliorates acute lung injury via inhibiting TH17 cells-NF-κB-dependent inflammation and activating the PI3K/Akt survival signaling pathway in mice

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T Cell Pathways Involving CTLA4 Contribute To a Model of Acute Lung Injury

Cited by 54 publications

References 34 publications

&alpha;-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

&alpha;-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

Regulation of Cytotoxic T Lymphocyte Antigen 4 by Cyclic AMP

KGF-2 ameliorates acute lung injury via inhibiting TH17 cells-NF-κB-dependent inflammation and activating the PI3K/Akt survival signaling pathway in mice

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α-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice

α-bisabolol-loaded lipid-core nanocapsules reduce lipopolysaccharide-induced pulmonary inflammation in mice