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. 2015 Oct;182(1):35-44.
doi: 10.1111/cei.12667. Epub 2015 Jul 19.

Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients

P Ruscitti  1 , P Cipriani  1 , P Di Benedetto  1 , V Liakouli  1 , O Berardicurti  1 , F Carubbi  1 , F Ciccia  2 , S Alvaro  1 , G Triolo  2 , R Giacomelli  1
Affiliations

Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients

P Ruscitti et al. Clin Exp Immunol. 2015 Oct.

Abstract

A better understanding about the mechanisms involved in the pathogenesis of type 2 diabetes mellitus (T2D) showed that inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin (IL)-1β play a pivotal role, mirroring data largely reported in rheumatoid arthritis (RA). IL-1β is produced mainly by monocytes (MO), and hyperglycaemia may be able to modulate, in the cytoplasm of these cells, the assembly of a nucleotide-binding domain and leucine-rich repeat containing family pyrin (NLRP3)-inflammosome, a cytosolic multi-protein platform where the inactive pro-IL-1β is cleaved into active form, via caspase-1 activity. In this paper, we evaluated the production of IL-1 β and TNF, in peripheral blood MO of patients affected by RA or T2D or both diseases, in order to understand if an alteration of the glucose metabolism may influence their proinflammatory status. Our data showed, after 24 h of incubation with different glucose concentrations, a significantly increased production of IL-1β and TNF in all evaluated groups when compared with healthy controls. However, a significant increase of IL-1β secretion by T2D/RA was observed when compared with other groups. The analysis of relative mRNA expression confirmed these data. After 24 h of incubation with different concentrations of glucose, our results showed a significant increase in NLRP3 expression. In this work, an increased production of IL-1β by MO obtained from patients affected by both RA and T2D via NLRP3-inflammasome activation may suggest a potential IL-1β targeted therapy in these patients.

Keywords: IL-1β; NLRP3-inflammasome; rheumatoid arthritis; type 2 diabetes mellitus.

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Figures

Figure 1
Figure 1
Increased secretion of interleukin (IL)-1β (a) and tumour necrosis factor (TNF) (b) after glucose stimulation in supernatants of cultured cells. Monocytes were incubated with 11 mmol/1 glucose (11G) and 33 mmol/1 glucose (33G) for 24 h. Our data showed that, after 24 h of incubation with 11G, a significant increase of IL-1β and TNF levels were shown when type 2 diabetes (T2D), rheumatoid arthritis (RA) and T2D/RA patients were compared with healthy controls (HC) (P < 0·01 for each comparison). After 24 h of incubation with 33G, a significant increase in IL-1β levels were observed in the supernatants of T2D/RA patients when compared with all evaluated groups (P < 0·01 for each comparison) (**P < 0·01).
Figure 2
Figure 2
Increased relative expression of interleukin (IL)-1β (a) and tumour necrosis factor (TNF) (b) after glucose stimulation in cultured cells. Monocytes were incubated with 11 mmol/1 glucose (11G) and 33 mmol/1 glucose (33G) for 24 h. Our data showed that, after 24 h of incubation with 11G, a significant increase of relative IL-1β and TNF mRNA expressions were reported when type 2 diabetes (T2D), rheumatoid arthritis (RA) and T2D/RA patients were compared with healthy controls (HC) (P < 0·001 for each comparison). However, after 24 h of incubation with 33G a significant increase in relative IL-1β mRNA expression was observed in the supernatants of T2D/RA patients when compared with HC and among other evaluated groups (P < 0·01 for each comparison) (***P < 0·001).
Figure 3
Figure 3
Increased relative expression of nucleotide-binding domain and leucine-rich repeat containing family pyrin (NLRP3) (a) after glucose stimulation and Western blot analyses (b). Monocytes were incubated with 11 mmol/1 glucose (G11), 33 mmol/1 glucose (G33). The expression levels of healthy controls (HC) incubated with 11 mmol/1 glucose (G11) were set to 100%, and the results were normalized to this value. Tubulin was measured as a loading control for normalization. After 24 h of incubation to 11G our results showed a significant increase in relative NLRP3 mRNA expression in type 2 diabetes/rheumatoid arthritis (T2D/RA) patients when compared with other groups (P < 0·001 for each comparison). After 24 h of incubation to 33G the results showed a significant increase in relative NLRP3 mRNA expression when we compared T2D/RA patients to other groups (P < 0·001 for each comparison). This analysis mirrored the results obtained by evaluation of NLRP3 mRNA expression by Western blot (**P < 0·01; ***P < 0·001, respectively).
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