Mycophenolic Acid Synergizing with Lipopolysaccharide to Induce Interleukin-1β Release via Activation of Caspase-1.

Xue-chan Huang; Yi HE; Jian Zhuang; Juan HE; Gui-hu Luo; Jiao-chan Han; Er-wei Sun

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Mycophenolic Acid Synergizing with Lipopolysaccharide to Induce Interleukin-1β Release via Activation of Caspase-1.

Author: Xue-Chan HUANG ¹ ; Yi HE ^{2
,

3} ; Jian ZHUANG ¹ ; Juan HE ¹ ; Gui-Hu LUO ¹ ; Jiao-Chan HAN ¹ ; Er-Wei SUN ^{2
,

3}
Author Information

1. Southern Medical University, Guangzhou, Guangdong 510515, China.
2. Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, China
3. Institute of Clinical Immunology, Academy of Orthopedics, Guangdong Province, Guangzhou, Guangdong 510630, China.
Publication Type:Journal Article
Keywords: Autoimmune Diseases; Caspase-1 Host Defense; Interleukin-1β; Lipopolysaccharide Mycophenolic Acid
MeSH: Animals; Caspase 1; metabolism; Cells, Cultured; Humans; Inflammasomes; Interleukin-1beta; metabolism; Lipopolysaccharides; pharmacology; Mice; Mice, Inbred NOD; Mycophenolic Acid; pharmacology; NLR Family, Pyrin Domain-Containing 3 Protein
From: Chinese Medical Journal 2018;131(13):1533-1540
CountryChina
Language:English
Abstract:
BackgroundThe previous study showed that mycophenolic acid (MPA) synergizing with lipopolysaccharide (LPS) promoted interleukin (IL)-1β release, but the mechanism is unclear. This study aimed to investigate the mechanism of MPA synergizing with LPS to induce IL-1β release.
MethodsUndiluted human blood cells, THP-1 human myeloid leukemia mononuclear cells (THP-1) cells, or monocytes were stimulated with LPS and treated with or without MPA, and the supernatant IL-1β was detected by enzyme-linked immunosorbent assay. The mRNA levels of IL-1β were detected by real-time quantitative polymerase chain reaction. The intracellular protein levels of nuclear factor kappa B (NF-κB) phospho-p65 (p-p65), precursor interleukin-1β (pro-IL-1β), NOD-like receptor pyrin domain containing-3 (NLRP3), and cysteine aspartic acid-specific protease-1 (caspase-1) p20 in THP-1 cell were measured by Western blot.
ResultsThe MPA alone failed to induce IL-1β, whereas MPA synergized with LPS to increase IL-1β in a dose-dependent manner (685.00 ± 20.00 pg/ml in LPS + 5 μmol/L MPA group, P = 0.035; 742.00 ± 31.58 pg/ml in LPS + 25 μmol/L MPA group, P = 0.017; 1000.00 ± 65.59 pg/ml in LPS + 75 μmol/L MPA group, P = 0.024; versus 408.00 ± 35.50 pg/ml in LPS group). MPA alone has no effect on the IL-1β mRNA expression, LPS induced the expression of IL-1β mRNA 2761 fold, and LPS + MPA increased the IL-1β expression 3018 fold, which had the same effect with LPS group (P = 0.834). MPA did not affect the intracellular NF-κB p-p65 and pro-IL-1β protein levels but activated NLRP3 inflammasome. Ac-YVAD-cmk blocked the activation of caspase-1 and subsequently attenuated IL-1β secretion (181.00 ± 45.24 pg/ml in LPS + MPA + YVAD group vs. 588.00 ± 41.99 pg/ml in LPS + MPA group, P = 0.014).
ConclusionsTaken together, MPA synergized with LPS to induce IL-1β release via the activation of caspase-1, rather than the enhanced production of pro-IL-1β. These findings suggested that patients immunosuppressed with mycophenolate mofetil may have overly activated caspase-1 during infection, which might contribute to a more sensitive host defense response to invading germs.