Monocyte deactivation in septic patients: Restoration by IFN-γ treatment
Abstract
Neutralization of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-alpha in vitro. This phenomenon of monocyte deactivation in septic patients with fatal outcome shows similarities to experimental monocytic refractoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-beta (TGF-beta). In order to strengthen their antimicrobial defense, here we tested whether interferon-gamma (IFN-gamma) can improve monocytic functions in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-alpha in these situations were significantly enhanced by IFN-gamma, but did not reach the extremely high levels of IFN-gamma primed naive cells from healthy donors. Moreover, IFN-gamma applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-gamma treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.
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Systemic production of IL-10 following the onset of a cytokine storm is a marker of a counter-anti-inflammatory response that has been termed 'immunoparalysis,' in that it is associated with downregulation of neutrophil and monocyte function in the systemic circulation.
“Systemic production of IL-10 following the onset of a cytokine storm is a marker of a counter-anti-inflammatory response that has been termed “immunoparalysis,” in that it is associated with downregulation of neutrophil and monocyte function in the systemic circulation (32,42,49).”
From Into the Eye of the Cytokine Storm (2012) · cites this paper as [42]
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- Authors
- Döcke, W.-D., Randow, F., Syrbe, U., Krausch, D., Asadullah, K., Reinke, P., Volk, H.-D., & Kox, W.
- Affiliations
- Humboldt-Universität zu Berlin (DE)
- Venue
- Nature Medicine
- Published
- 1997-06
- Volume
- 3
- Issue
- 6
- Pages
- 678-681
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1972757665
- Cited by
- 1,190
- References
- 21
- Citations by year
- 2026: 27 · 2025: 31 · 2024: 26 · 2023: 32 · 2022: 29 · 2021: 35 · 2020: 43 · 2019: 34 · 2018: 31 · 2017: 33 · 2016: 37 · 2015: 36 · 2014: 42 · 2013: 50 · 2012: 43
- FWCI
- 33.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- sepsis, interferon-gamma therapy, HLA-DR expression, TNF-α, lipopolysaccharide, IL-10, TGF-beta, opportunistic infections, sepsis mortality
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, HLA-DR Antigens, Humans, Interferon-gamma, Leukocytes, Mononuclear, Lipopolysaccharides, Middle Aged, Monocytes, Tumor Necrosis Factor-alpha, Sepsis
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