Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes.

Mehrotra, P T; Wu, Di; Crim, John A.; Mostowski, Howard; Siegel, Jay P.

doi:10.4049/jimmunol.151.5.2444

Cited by 177 publications

(7 citation statements)

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“…IL-12 has also been suggested to functionally modulate the neutrophils recruited to the primary tumor toward antitumor properties. IL-12 was shown in various studies to activate antitumor immunity in many ways, including the activation of NK cells, modulation of activated CD4 + T lymphocytes to become Th1 cells, and activation of CD8 + cytotoxic T lymphocytes [183,184]. Treatment combining cyclophosphamide and IL-12 in a colon cancer mouse model was reported to induce an increase in TANs with antitumor properties, with increased expression of proinflammatory cytokines IL-1, IL-6, IL-12, CCL5, and CCL3 [185].…”

Section: Functional Plasticity -N1 Vs N2mentioning

confidence: 99%

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

2018

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In recent years, the role of neutrophils in cancer biology has been a matter of increasing interest. Many patients with advanced cancer show high levels of neutrophilia, tumor neutrophils are connected to dismal prognosis, and the neutrophil-to-lymphocyte ratio has been introduced as a significant prognostic factor for survival in many types of cancer. Neutrophils constitute an important portion of the infiltrating immune cells in the tumor microenvironment, but controversy has long surrounded the function of these cells in the context of cancer. Multiple evidences have shown that neutrophils recruited to the tumor can acquire either protumor or antitumor function. These findings have led to the identification of multiple and heterogeneous neutrophil subsets in the tumor and circulation. In addition, tumor-associated neutrophils (TANs) were shown to demonstrate functional plasticity, driven by multiple factors present in the tumor microenvironment. In this review, we examine the current knowledge on cancer-related circulating neutrophils, their source and the function of the different subtypes, both mature and immature. We then discuss the pro vs antitumor nature of TANs in cancer, their functional plasticity and the mechanisms that regulate neutrophil recruitment and polarization. Although the vast majority of the knowledge on neutrophils in cancer comes from murine studies, recent work has been done on human cancer-related neutrophils. In the final paragraphs, we expand on the current knowledge regarding the role of neutrophils in human cancer and examine the question whether cancer-related neutrophils (circulating or intratumoral) could be a new possible target for cancer immunotherapy.

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Section: Functional Plasticity -N1 Vs N2mentioning

confidence: 99%

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

2018

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“…A study revealed (Mehrotra et al, 1993) that macroscopic findings in squirrel monkeys dosed with 50 μg/kg of IL‐12 per day included pulmonary edema and pleural and peritoneal effusions. In addition, generalized dose‐dependent lymph node enlargement and splenomegaly occurred in monkeys dosed with rhIL‐12.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that the toxicity of IL‐12 is partly due to its ability to stimulate the production of other cytokines such as interferon‐gamma and tumor necrosis factor‐alpha, which can cause inflammation and tissue damage. In addition, IL‐12 has been found to activate immune cells known as regulatory T cells, which can suppress immune responses and contribute to cytokine toxicity (Mehrotra et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

The repeated administration of rhIL‐12 for 14 weeks in rhesus monkeys: A toxicity assessment

Ding,

Qin,

Wang

et al. 2023

J of Applied Toxicology

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Interleukin‐12 (IL‐12) is known to exert antitumor immune effects by promoting the activation and proliferation of T cells and NK cells within the immune system. However, clinical trials have observed systemic toxicity associated with the administration of IL‐12. This has shelved development plans for its use as a cancer therapeutic drug. Therefore, it is critical that we perform a systematic evaluation of the toxicity and safety of repeated IL‐12 administration. In this study, we conducted a comprehensive evaluation of the toxicity and safety of repeated rhIL‐12 (recombinant human interleukin‐12) administration in rhesus monkeys by assessing its effects on the immune system, organ function, and vital signs. Rhesus monkeys were subcutaneously injected with 0.5, 2.5, and 12.5 μg/kg of rhIL‐12 for up to for 14 consecutive weeks. The low dose exhibited no signs of toxicity, whereas animals receiving higher doses displayed symptoms such as loose stools, reduced activity, anemia, and elevated liver function indicators (AST and TBIL). Following three administrations of 12.5 μg/kg, high dosing was adjusted to 7.5 μg/kg due to manifestations of symptoms like loose stools, decreased activity, and huddling in the cage. Furthermore, rhesus monkeys exhibited marked immunogenic responses to recombinant human interleukin‐12 (rhIL‐12). However, based on overall study findings, the No Observed Adverse Effect Level (NOAEL) for the subcutaneous injection of rhIL‐12, when repeatedly administered for 3 months in rhesus monkeys, was considered to be 0.5 μg/kg. The Highest Non‐Severely Toxic Dose (HNSTD) was considered to be 7.5 μg/kg.

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“…Some scholars have shown that NP can inhibit the mitosis of lymphocytes by acting on ER-α on mouse T cells and B cells, reducing the number of effector cells produced by T cells and B cells, and ultimately affecting the immune function [94,103]. In addition, studies have found that estrogen stimulated expressions of IFN-γ and IL-12 in CD8 + T cells, thereby enhancing the activity of B lymphocytes [104,105]. IL-12 is an important initiator of cellular immune responses, as demonstrated by high-throughput sequencing results detecting upregulation of the immune factors TNF-a and IL10 in IL12 downregulation experiments [106,107].…”

Section: Discussionmentioning

confidence: 99%

Effects of subchronic exposure of nonylphenol on the expression of immune-related factors and estrogen receptors in the spleen of rats

et al. 2022

Environ Sci Eur

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Background Previous studies have shown that EDCs may activate nuclear transcription factor, such as activator protein-1 (AP-1), nuclear factor of activated Tcells (NF-AT) and nuclear factor kappa B (NF-κB) in the process of immune damage. At the same time, some experts believed that estrogen may play an important role in this process. As a typical representative of EDCs, nonylphenol (NP) has not been reported. The aim of this work was to explore the relationship between the immune inflammatory damage and the changes in estrogen expression in male rats during the chronic exposure to NP at environmental concentrations. Sixty SPF Sprague–Dawley rats were divided into five groups (n = 12 per group): blank control group (corn oil), low-dose NP exposure group (0.4 mg/kg/d), medium-dose NP exposure group (4 mg/kg/d), high-dose NP exposure group (40 mg/kg/d), and estradiol control group (E2: 30 μg/kg/d). Results Compared with the control group, rat spleen organ coefficient, number of spleen nodules, relative area of lymph nodes and white pulp were relatively reduced in the L (NP, 0.4 mg/kg) and H (NP, 40 mg/kg) exposure dose groups (P < 0.001). Lymphocytes were rich in cytoplasm, mitochondria were swollen, part of the cristae was reduced, and rough endoplasmic reticulum was expanded. The serum levels of IgG (P < 0.001) and IgM (P = 0.002) showed a downward trend. The percentage of Th cells (CD3+CD4+) was significantly decreased (P < 0.001), and the percentage of B lymphocytes shows an opposite trend (P < 0.001). Giemsa staining showed that the number of neutrophils (P < 0.001) was increased. The expressions of estrogen receptor ER-α and ER-β protein in the spleen increased significantly (P < 0.001). The expressions of AP-1 protein and NF-AT protein in the spleen were increased, and the expression of NF-KB protein was decreased (P < 0.001). The expressions of IL-4, ER-α and ER-β (P < 0.001) levels in serum increased. The mRNA-seq bioinformatics detection showed the final differentially expressed immune-inflammatory-related genes between the control and H-NP groups as follow: down-regulated: TLR4, Gata3, IL12, up-regulated: TNF-a, IL10, INOS. The mRNA expressions of ER-α, ER-β, NF-KB, IL4, AP-1, TLR4, Gata3, and NF-AT were consistent with the results of mRNA-seq analysis. NP content was correlated with the expressions of ER-α, ER-β, IL4, AP-1, NF-AT, TLR4, NF-KB, as well as IL-12 proteins in the spleen tissue ([r] < 1, P < 0.05). Conclusions Chronic exposure to NP at environmental concentration could cause immune dysfunction, resulting in immunotoxicity and inflammatory effects, and lead to changes in the activity of transcription factors and differential immune inflammatory factors in rats. Graphical Abstract

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Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes.

Cited by 177 publications

References 0 publications

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

The repeated administration of rhIL‐12 for 14 weeks in rhesus monkeys: A toxicity assessment

Effects of subchronic exposure of nonylphenol on the expression of immune-related factors and estrogen receptors in the spleen of rats

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