Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cytokine activation of NK cell glycolysis and oxidative phosphorylation (OXPHOS) are essential for robust NK cell ...responses. However, the mechanisms leading to this metabolic phenotype are unclear. Here we show that the transcription factor cMyc is essential for IL-2/IL-12-induced metabolic and functional responses in mice. cMyc protein levels are acutely regulated by amino acids; cMyc protein is lost rapidly when glutamine is withdrawn or when system L-amino acid transport is blocked. We identify SLC7A5 as the predominant system L-amino acid transporter in activated NK cells. Unlike other lymphocyte subsets, glutaminolysis and the tricarboxylic acid cycle do not sustain OXPHOS in activated NK cells. Glutamine withdrawal, but not the inhibition of glutaminolysis, results in the loss of cMyc protein, reduced cell growth and impaired NK cell responses. These data identify an essential role for amino acid-controlled cMyc for NK cell metabolism and function.
The aryl hydrocarbon receptor (AHR) is widely expressed in immune and non-immune cells of the gut and its activation has been correlated to the outcome of inflammatory bowel diseases (IBD). In ...ulcerative colitis and Crohn’s disease, there is an excessive chronic inflammation with massive accumulation of leukocytes in the gut, in an attempt to constrain the invasion of pathogenic microorganisms on the damaged organ. Accordingly, it is known that dietary components, xenobiotics, and some chemicals or metabolites can activate AHR and induce the modulation of inflammatory responses. In fact, the AHR triggering by specific ligands during inflammatory conditions results in decreased IFNγ, IL-6, IL-12, TNF, IL-7, and IL-17, along with reduced microbial translocation and fibrosis in the gut. Moreover, upon AHR activation, there are increased regulatory mechanisms such as IL-10, IL-22, prostaglandin E
2
, and Foxp3, besides the production of anti-microbial peptides and epithelial repair. Most interestingly, commensal bacteria or their metabolites may also activate this receptor, thus contributing to the restoration of gut normobiosis and homeostasis. In line with that,
Lactobacillus reuteri
,
Lactobacillus bulgaricus
, or microbial products such as tryptophan metabolites, indole-3-pyruvic acid, urolithin A, short-chain fatty acids, dihydroxyquinoline, and others may regulate the inflammation by mechanisms dependent on AHR activation. Hence, here we discussed the potential modulatory role of AHR on intestinal inflammation, focused on the reestablishment of homeostasis through the receptor triggering by microbial metabolites. Finally, the development of AHR-based therapies derived from bacteria products could represent an important future alternative for controlling IBD.
Dendritic cells (DC) are professional antigen-presenting cells that orchestrate immune responses. The human DC population comprises two main functionally specialized lineages, whose origins and ...differentiation pathways remain incompletely defined. Here, we combine two high-dimensional technologies-single-cell messenger RNA sequencing (scmRNAseq) and cytometry by time-of-flight (CyTOF)-to identify human blood CD123
CD33
CD45RA
DC precursors (pre-DC). Pre-DC share surface markers with plasmacytoid DC (pDC) but have distinct functional properties that were previously attributed to pDC. Tracing the differentiation of DC from the bone marrow to the peripheral blood revealed that the pre-DC compartment contains distinct lineage-committed subpopulations, including one early uncommitted CD123
pre-DC subset and two CD45RA
CD123
lineage-committed subsets exhibiting functional differences. The discovery of multiple committed pre-DC populations opens promising new avenues for the therapeutic exploitation of DC subset-specific targeting.
Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. ...High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.
Macrophages have been shown to demonstrate a high level of plasticity, with the ability to undergo dynamic transition between M1 and M2 polarized phenotypes. We investigate long non‐coding RNA ...(lncRNA) cox‐2 in macrophage polarization and the regulatory mechanism functions in hepatocellular carcinoma (HCC). Lipopolysaccharide (LPS) was used to induce RAW264.7 macrophages into M1 type, and IL‐4 was to induce RAW264.7 macrophages into M2 type. We selected mouse hepatic cell line Hepal‐6 and hepatoma cell line HepG2 for co‐incubation with M1 or M2 macrophages. Quantitative real‐time PCR was used to detect the expressions of lncRNA cox‐2 and mRNAs. ELISA was conducted for testing IL‐12 and IL‐10 expressions; Western blotting for epithelial mesenchymal transition related factors (E‐cadherin and Vimentin). An MTT, colony formation assay, flow cytometry, transwell assay, and stretch test were conducted to test cell abilities. The M1 macrophages had higher lncRNA cox‐2 expression than that in the non‐polarized macrophages and M2 macrophages. The lncRNA cox‐2 siRNA decreased the expression levels of IL‐12, iNOS, and TNF‐α in M1 macrophages, increased the expression levels of IL‐10, Arg‐1, and Fizz‐1 in M2 macrophages (all P < 0.05). The lncRNA cox‐2 siRNA reduces the ability of M1 macrophages to inhibit HCC cell proliferation, invasion, migration, EMT, angiogenesis and facilitate apoptosis while strengthening the ability of M2 macrophages to promote proliferation HCC cell growth and inhibit apoptosis. These findings indicate that lncRNA cox‐2 inhibits HCC immune evasion and tumor growth by inhibiting the polarization of M2 macrophages.
Human interleukin-12 (hIL-12) is a cytokine with anticancer activity, but its systemic application is limited by toxic inflammatory responses. We assessed the safety and biological effects of an ...hIL-12 gene, transcriptionally regulated by an oral activator. A multicenter phase 1 dose-escalation trial (NCT02026271) treated 31 patients undergoing resection of recurrent high-grade glioma. Resection cavity walls were injected (day 0) with a fixed dose of the hIL-12 vector (Ad-RTS-hIL-12). The oral activator for hIL-12, veledimex (VDX), was administered preoperatively (assaying blood-brain barrier penetration) and postoperatively (measuring hIL-12 transcriptional regulation). Cohorts received 10 to 40 mg of VDX before and after Ad-RTS-hIL-12. Dose-related increases in VDX, IL-12, and interferon-γ (IFN-γ) were observed in peripheral blood, with about 40% VDX tumor penetration. Frequency and severity of adverse events, including cytokine release syndrome, correlated with VDX dose, reversing promptly upon discontinuation. VDX (20 mg) had superior drug compliance and 12.7 months median overall survival (mOS) at mean follow-up of 13.1 months. Concurrent corticosteroids negatively affected survival: In patients cumulatively receiving >20 mg versus ≤20 mg of dexamethasone (days 0 to 14), mOS was 6.4 and 16.7 months, respectively, in all patients and 6.4 and 17.8 months, respectively, in the 20-mg VDX cohort. Re-resection in five of five patients with suspected recurrence after Ad-RTS-hIL-12 revealed mostly pseudoprogression with increased tumor-infiltrating lymphocytes producing IFN-γ and programmed cell death protein 1 (PD-1). These inflammatory infiltrates support an immunological antitumor effect of hIL-12. This phase 1 trial showed acceptable tolerability of regulated hIL-12 with encouraging preliminary results.
The immune status of the tumor microenvironment is a key indicator in determining the antitumor effectiveness of immunotherapies. Data support the role of activation and expansion of ...tumor-infiltrating lymphocytes (TILs) in increasing the benefit of immunotherapies in patients with solid tumors. We found that intratumoral injection of a tumor-selective oncolytic vaccinia virus encoding interleukin-7 (IL-7) and IL-12 into tumor-bearing immunocompetent mice activated the inflammatory immune status of previously poorly immunogenic tumors and resulted in complete tumor regression, even in distant tumor deposits. Mice achieving complete tumor regression resisted rechallenge with the same tumor cells, suggesting establishment of long-term tumor-specific immune memory. Combining this virotherapy with anti-programmed cell death-1 (PD-1) or anti-cytotoxic T lymphocyte antigen 4 (CTLA4) antibody further increased the antitumor activity as compared to virotherapy alone, in tumor models unresponsive to either of the checkpoint inhibitor monotherapies. These findings suggest that administration of an oncolytic vaccinia virus carrying genes encoding for IL-7 and IL-12 has antitumor activity in both directly injected and distant noninjected tumors through immune status changes rendering tumors sensitive to immune checkpoint blockade. The benefit of intratumoral IL-7 and IL-12 expression was also observed in humanized mice bearing human cancer cells. These data support further investigation in patients with non-inflamed solid tumors.
Tumor-associated immune response plays a critical role in cancer pathogenesis. This study evaluated clinical implications of T cell cytokines and regulatory T cells (Tregs) in HCC patients treated ...with TACE. Whole blood was obtained for analysis of T cell cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-22, IFN-γ, and TNF-α) and Tregs from 142 HCC patients. Patients with CTP class A had a significantly lower proportion of detectable IL-4 or IL-6, but a higher proportion of detectable IL-22 than patients with CTP class B/C. IL-6 level was well correlated with tumor stage and undetectable IL-17A was associated with extrahepatic metastasis. The overall survival rate was significantly higher in patients who had undetectable IL-6 or detectable IL-22 than patients who did not. IL-6 among cytokines remained independently predictive factor for survival. Increased IFN-γ/IL-10 ratio and no increase in IL-6 level following TACE were associated with prolonged survival, and baseline Tregs could affect Th1/Th2 balance. T cell cytokines are associated with a variety of clinical aspects of HCC, and IL-6 is the most significant predictor of survival. A shift toward increased Th1 response and no increase in IL-6 level exert favorable immunologic effects on HCC prognosis.
Berberine hydrochloride is one the effective compound among Rhizoma Coptidis, Cortex Phellodendri, and other plants. There are several clinical functions of berberine hydrochloride including ...anti-inflammation, antitumor and immunoregulatory. However, the anti-inflammatory of berberine hydrochloride in ulcerative colitis is barely understood. In this study, we aimed to explore the effects of berberine hydrochloride on dextran sulfate sodium (DSS)-induced rats model of ulcerative colitis.
The severity of colitis were measured by body weight, survial rate, colon length and disease activity index (DAI) score. The cytokines expression include IL-1, IL-1β, IL-4, IL-6, IL-10, IL-12, TNF-α, TGF-β and IFN-γ were performed by RT-PCR and ELISA. Signaling pathway proteins such as p-STAT3, STAT3, p-NF-κB p65 and NF-κB p65 were analyzed by western blot and immunofluorescence. The proteins expression of tight junction were explored using western blotting and immunohistochemistry.
Rats were administered berberine hydrochloride showed less weight loss and longer colon length than the DSS-induced group. The expression of IL-1, IL-1β, IL-6, IL-12, TNF-α, TGF-β and IFN-γ were suppressed, yet the expression of IL-4 and IL-10 were up-regulated by berberine hydrochloride and sulphasalazine treatment compared to the model group. Meanwhile, treatment with berberine hydrochloride effectively increased the expression of SIgA and decreased the expression of iNOS, MPO, MDA. In terms of the biochemical analyses, the results showed that the expression of p-STAT3 was signifcantly increased, while the expression of p-NF-κB (p65) was suppressed compared to the model group via western blot and immunofluorescence analysis.
Berberine hydrochloride has beneficial effects in UC. The possible mechanism of anti-inflammatory response by berberine hydrochloride may involve in the blocking of the IL-6/STAT3/NF-κB signaling pathway. Collectively, these fndings provide evidence that berberine hydrochloride might be a useful herb medicine and serve as a promising novel therapy in the treatment of UC in humans.
•Berberine hydrochloride has the anti-inflammatory effect in ulcerative colitis.•Berberine hydrochloride could suppress apoptosis in ulcerative colitis.•Berberine hydrochloride has protective effects on DSS-induced ulcerative colitis via IL-6/STAT3/NF-κB pathway in rats.
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