IL-18/IL-15/IL-12 synergy induces elevated and prolonged IFN-γ production by ex vivo expanded NK cells which is not due to enhanced STAT4 activation

Lusty, Evan; Poznanski, Sophie M.; Kwofie, Karen; Mandur, Talveer S.; Lee, Dean A.; Richards, Carl D.; Ashkar, Ali A.

doi:10.1016/j.molimm.2017.06.025

Cited by 72 publications

(55 citation statements)

References 31 publications

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“…The type 1 cytokine, IL‐18, enhances expression of IFNG by IL‐12‐stimulated human NK cells 30 in part via p38 MAPK stabilization of IFNG transcripts 23 . Our data suggest that a type 2 cytokine, IL‐33, similarly enhances IL‐12‐induced IFN‐γ expression by human NK cells.…”

Section: Discussionmentioning

confidence: 63%

“…Moreover, enhanced TNF secretion was partially attributable to ADAM17. These results highlight the possibility for exaggerated cytokine secretion by human NK cells in physiological setting that are characterized by dual exposure to type 1 (IL-12) and type 2 (IL-33) cytokines.The type 1 cytokine, IL-18, enhances expression of IFNG by IL-12stimulated human NK cells30 in part via p38 MAPK stabilization of IFNG transcripts 23. Our data suggest that a type 2 cytokine, IL-33, similarly enhances IL-12-induced IFN-expression by human NK cells.Moreover, IL-33 amplification of IFN-is dependent on p38 MAPK activity and associated with increased stability of IFNG mRNA.…”

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confidence: 57%

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IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Ochayon

Ali

Alarcon

et al. 2020

Journal of Leukocyte Biology

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This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL‐33 contributes to enhanced cytokine expression by IL‐12 stimulated human NK cells. While IL‐33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL‐12 to provoke IFN‐γ. We show that picogram concentrations of IL‐12 and IL‐33 are sufficient to promote robust secretion of IFN‐γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL‐33, potentially consistent with levels in tissue microenvironments, synergize with IL‐12 to induce secretion of additional cytokines, including TNF and GM‐CSF. IL‐33‐induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN‐γ and TNF in response to IL‐12. Mechanistically, IL‐33‐induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL‐12 in the presence of IL‐33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.

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Section: Discussionmentioning

confidence: 63%

mentioning

confidence: 57%

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Ochayon

Ali

Alarcon

et al. 2020

Journal of Leukocyte Biology

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“…Trans-presentation of IL-15 by IL-15Ra to NK cells induces NK cell activation, proliferation, transcriptional reprogramming, and other effector functions 103. The IL-12 family cytokines, IL-12, IL-23, IL-27, and IL-35, have been demonstrated to induce NK activation and functions, such as IFN-secretion, or may via synergize with other cytokines such as IL-2 to activate NK cell 104. Indirect NK cell activation during viral and bacterial infection has been extensively studied.…”

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confidence: 99%

Microbial killing by NK cells

Mody

Ogbomo

Xiang

et al. 2019

Journal of Leukocyte Biology

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It is now evident that NK cells kill bacteria, fungi, and parasites in addition to tumor and virus‐infected cells. In addition to a number of recent publications that have identified the receptors and ligands, and mechanisms of cytotoxicity, new insights are reflected in the reports from researchers all over the world at the 17th Meeting of the Society for Natural Immunity held in San Antonio, TX, USA from May 28 through June 1, 2018. We will provide an overview of the field and discuss how the presentations at the meeting might shape our knowledge and future directions in the field.

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“…IFNγ inhibits the infection of cytomegalovirus, while IL18 can facilitate the secretion of IFNγ to control virus infections [21, 22]. Although IL10 is usually considered to be a suppressor for host immunity, it actually has a complicated role in MCMV infection [23, 24].…”

Section: Resultsmentioning

confidence: 99%

“…NK cells might be the source of IFNγ during the first 3 days postinfection and T cells expressed IFNγ at a later stage [9]. IL18 is a crucial immune factor which facilitates secretion of IFNγ to control virus infections [22, 39]. IL10 is usually secreted by Th2 cells, but NK cells and CD8 T cells also occasionally express IL10 [23, 24].…”

Section: Discussionmentioning

confidence: 99%

The Effects of IL10 and NK Cells on the Susceptibility to Mouse Cytomegalovirus in BALB/c Mice despite the Compensation of IFNγ

Lu¹,

Liu²,

Huang³

et al. 2018

Intervirology

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Objective: The aim of this study was to determine which factors lead to the susceptibility to mouse cytomegalovirus (MCMV) in the spleens of BALB/c mice. Methods: BALB/c and C57BL/6 mice were randomly divided into a control group and an infection group and sacrificed on day 0, 1, 3, 7, 14, and 28 postinfection. The cytotoxicity of NK cells was determined by evaluating lactate dehydrogenase contents. Flow cytometry was used to analyze activated NK cells, IFNγ⁺ NK cells, and total NK cells in the spleen. The pathological changes of spleens in each group were analyzed by HE staining. The expression of IL10, IL18, IFNγ, Thpok, and IFNβ of spleens was determined by quantitative reverse transcriptase PCR. The viral loads of MCMV in spleens and salivary glands were also detected. Results: We found that spleen NK cells and IL10 in C57BL/6 mice possessed more powerful immunity to MCMV than BALB/c mice. In BALB/c mice, combined effects of the cytotoxicity of NK cells and IFNγ in spleens still ended up with deficient control of infection. Conclusion: The functional shortage of NK cells and inappropriate expression of IL10 result in the susceptibility to MCMV in BALB/c mice.

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IL-18/IL-15/IL-12 synergy induces elevated and prolonged IFN-γ production by ex vivo expanded NK cells which is not due to enhanced STAT4 activation

Cited by 72 publications

References 31 publications

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Microbial killing by NK cells

The Effects of IL10 and NK Cells on the Susceptibility to Mouse Cytomegalovirus in BALB/c Mice despite the Compensation of IFNγ

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