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The effect of IκK-16 on lipopolysaccharide-induced impaired monocytes
Norman J Galbraith1, Stephen Manek1, Samuel Walker1
1Price Institute of Surgical Research, Department of Surgery, University of Louisville School of Medicine, USA.
Abstract:
This study focuses on impaired monocyte function, which occurs in some patients after trauma, major elective surgery, or sepsis. This monocyte impairment increases the risk of secondary infection and death. We aimed to determine the influence IκK-16 had on monocytes using an ex-vivo model of human monocyte impairment. We included the effects of the well-studied comparators interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on impaired monocytes. Primary human monocytes were stimulated with 10ng/mL of lipopolysaccharide (LPS) for 16h and then challenged with 100ng/mL LPS to assess the monocyte inflammatory response. Treatment regimens, consisting of either IκK-16, IFN-γ, or GM-CSF, were administered to impaired monocytes near the time of initial LPS stimulation. Stimulation with 10ng/mL LPS initially promoted a pro-inflammatory response but subsequently impaired production of both tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) and decreased HLA-DR expression. IκK-16 treatment attenuated TNF-α production and programmed death-ligand 1 (PD-L1) expression and increased IL-10 and CD14 expression. IFN-γ treatment increased TNF-α production as well as PD-L1 and HLA-DR expression. In conclusion, limiting early inflammation with IκK-16 suppresses TNF-α production and PD-L1 expression but enhances IL-10 production and preserves CD14 expression for potential future exposure to infective stimuli.
Insights
IκK-16 treatment in impaired human monocytes reduced inflammatory tumor necrosis factor-alpha (TNF-α) and programmed death-ligand 1 (PD-L1) while increasing anti-inflammatory interleukin-10 (IL-10) and CD14 expression.
Area of Science:
- Immunology
- Cellular Biology
- Infectious Disease Research
Background:
- Monocyte dysfunction following trauma, surgery, or sepsis elevates secondary infection and mortality risks.
- Impaired monocyte function is characterized by altered inflammatory responses and reduced immune marker expression.
- Understanding modulators of monocyte function is critical for improving patient outcomes in critical care settings.
Purpose of the Study:
- To investigate the effect of IκK-16 on ex-vivo human monocyte impairment.
- To compare IκK-16's influence with established immune modulators, interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF).
- To assess the impact on key inflammatory and immune markers in a lipopolysaccharide (LPS)-induced monocyte impairment model.
Main Methods:
- Primary human monocytes were stimulated with lipopolysaccharide (LPS) to induce impairment.
- Impaired monocytes were treated with IκK-16, IFN-γ, or GM-CSF.
- The production of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), HLA-DR, programmed death-ligand 1 (PD-L1), and CD14 expression were analyzed.
Main Results:
- LPS stimulation initially induced inflammation but impaired subsequent TNF-α and IL-10 production and decreased HLA-DR expression.
- IκK-16 treatment attenuated TNF-α and PD-L1 expression while increasing IL-10 and CD14 expression.
- IFN-γ treatment enhanced TNF-α, PD-L1, and HLA-DR expression.
Conclusions:
- IκK-16 limits early inflammation by suppressing TNF-α and PD-L1, and enhances IL-10 production in impaired monocytes.
- IκK-16 preserves CD14 expression, potentially supporting responses to future infections.
- IκK-16 demonstrates a distinct immunomodulatory profile compared to IFN-γ in this ex-vivo model.
