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Spontaneous cytokine production and its effect on induced production
Derrick Walker1, Janine Jason, Kelly Wallace
1Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia 30333, USA. ziq4@cdc.gov
Insights
Spontaneous cytokine production by immune cells is common in acutely ill individuals and healthy adults in endemic areas. This study highlights the importance of measuring both spontaneous and induced cytokine levels in disease states.
Area of Science:
- Immunology
- Cellular Biology
- Infectious Disease Research
Background:
- Cytokines are crucial for immune regulation, produced by various immune cells like lymphocytes and monocytes.
- Standard methods for studying cytokine production involve in vitro induction and protein secretion inhibition.
- Spontaneous ex vivo cytokine production is generally considered rare.
Purpose of the Study:
- To investigate the spontaneous production of key cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma) by different peripheral blood immune cell subsets.
- To compare spontaneous cytokine production between acutely ill hospitalized patients and healthy adults in Malawi.
- To evaluate the relationship between spontaneous and induced cytokine production in these populations.
Main Methods:
- Multiparameter flow cytometry was used to analyze spontaneous cytokine production.
- Immune cell subsets analyzed included B lymphocytes, T cells (CD8(-), CD8(+)), NK cells, NT cells, and monocytes.
- Cytokine levels were measured in 316 acutely ill patients and 62 healthy adults in Malawi, an area endemic for various infections.
Main Results:
- Spontaneous tumor necrosis factor alpha (TNF-alpha) was the most frequent cytokine produced by patients, followed by IFN-gamma, IL-8, IL-4, IL-10, IL-6, and IL-2.
- Spontaneous cytokine production was most prevalent in natural killer (NK) and natural T (NT) cells.
- In healthy adults, IL-6 was the most commonly spontaneously produced cytokine.
- Spontaneous production correlated with greater induced production for IL-2, IL-4, IL-6, IL-8, and IL-10, with varied relationships for TNF-alpha and IFN-gamma.
Conclusions:
- Spontaneous cytokine production is not unusual in individuals living in regions endemic for HIV, malaria, and parasitic infections.
- Both spontaneous and induced cell-specific cytokine production should be assessed in relation to disease states in these populations.
- Findings challenge the notion that spontaneous cytokine production is rare, particularly in specific immune cell types and disease contexts.
Abstract:
Cytokines regulate cellular immune activity and are produced by a variety of cells, especially lymphocytes, monocytes, and macrophages. Multiparameter flow cytometry is often used to examine cell-specific cytokine production after in vitro phorbol 12-myristate 13-acetate and ionomycin induction, with brefeldin A or other agents added to inhibit protein secretion. Spontaneous ex vivo production reportedly rarely occurs. We examined the spontaneous production of interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma) by peripheral-blood B lymphocytes, T cells, CD8(-) T cells, CD8(+) T cells, CD3(-) CD16/56(+) lymphocytes (natural killer [NK] cells), CD3(+) CD16/56(+) lymphocytes (natural T [NT] cells), and/or monocytes of 316 acutely ill hospitalized persons and 62 healthy adults in Malawi, Africa. We also evaluated the relationship between spontaneous and induced cytokine production. In patients, spontaneous TNF-alpha production occurred most frequently, followed in descending order by IFN-gamma, IL-8, IL-4, IL-10, IL-6, and IL-2. Various cells of 60 patients spontaneously produced TNF-alpha; for 12 of these patients, TNF-alpha was the only cytokine produced spontaneously. Spontaneous cytokine production was most frequent in the immunoregulatory cells, NK and NT. For IL-2, IL-4, IL-6, IL-8, and IL-10, spontaneous cytokine production was associated with greater induced production. For TNF-alpha and IFN-gamma, the relationships varied by cell type. For healthy adults, IL-6 was the cytokine most often produced spontaneously. Spontaneous cytokine production was not unusual in these acutely ill and healthy persons living in an area where human immunodeficiency virus, mycobacterial, malaria, and assorted parasitic infections are endemic. In such populations, spontaneous, as well as induced, cell-specific cytokine production should be measured and evaluated in relation to various disease states.
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