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2017 ; 18
(1
): 131
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Azithromycin decreases NALP3 mRNA stability in monocytes to limit
inflammasome-dependent inflammation
#MMPMID28659178
Lendermon EA
; Coon TA
; Bednash JS
; Weathington NM
; McDyer JF
; Mallampalli RK
Respir Res
2017[Jun]; 18
(1
): 131
PMID28659178
show ga
BACKGROUND: Azithromycin, an antibiotic used for multiple infectious disorders,
exhibits anti-inflammatory effects, but the molecular basis for this activity is
not well characterized. Azithromycin inhibits IL-1?-mediated inflammation that is
dependent, in part, on inflammasome activity. Here, we investigated the effects
of azithromycin on the NACHT, LRR, and PYD domains-containing protein 3 (NALP3)
protein, which is the sensing component of the NALP3 inflammasome, in human
monocytes. METHODS: THP-1 cells were treated with azithromycin alone, LPS alone,
or both. NALP3 and IL-1? protein levels were determined by immunoblotting. NLRP3
gene (encoding NALP3) transcript levels were determined by quantitative qPCR. In
order to measure NLRP3 transcript decay, actinomycin D was used to impair gene
transcription. THP-1 Lucia cells which contain an NF-?B responsive luciferase
element were used to assess NF-?B activity in response to azithromycin, LPS, and
azithromycin/LPS by measuring luminescence. To confirm azithromycin's effects on
NLRP3 mRNA and promoter activity conclusively, HEK cells were lipofected with
luciferase reporter constructs harboring either the 5' untranslated region (UTR)
of the NLRP3 gene which included the promoter, the 3' UTR of the gene, or an
empty plasmid prior to treatment with azithromycin and/or LPS, and luminescence
was measured. RESULTS: Azithromycin decreased IL-1? levels and reduced NALP3
protein levels in LPS-stimulated THP-1 monocytes through a mechanism involving
decreased mRNA stability of the NALP3 - coding NLRP3 gene transcript as well as
by decreasing NF-?B activity. Azithromycin accelerated NLRP3 transcript decay
confirmed by mRNA stability and 3'UTR luciferase reporter assays, and yet the
antibiotic had no effect on NLRP3 promoter activity in cells containing a 5' UTR
reporter. CONCLUSIONS: These studies provide a unique mechanism whereby
azithromycin exerts immunomodulatory actions in monocytes by destabilizing mRNA
levels for a key inflammasome component, NALP3, leading to decreased
IL-1?-mediated inflammation.
|Anti-Bacterial Agents/pharmacology/therapeutic use
[MESH]
|Azithromycin/*pharmacology/therapeutic use
[MESH]
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