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

Abstract

BACKGROUND:

The 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.

METHODS:

Undiluted 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.

RESULTS:

The 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).

CONCLUSIONS:

Taken 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.

• Authors: Xue-Chan Huang, Yi He, Jian Zhuang, Juan He, Gui-Hu Luo, Jiao-Chan Han, Er-Wei Sun
• Journal: Chinese medical journal (Chin Med J (Engl)) Vol. 131 Issue 13 Pg. 1533-1540 (Jul 05 2018) ISSN: 2542-5641 [Electronic] China
• PMID: 29941706 (Publication Type: Journal Article)

Chemical References

• Inflammasomes
• Interleukin-1beta
• Lipopolysaccharides
• NLR Family, Pyrin Domain-Containing 3 Protein
• Caspase 1
• Mycophenolic Acid

Topics

• 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