Upregulation of miR-196b-5p attenuates BCG uptake via targeting SOCS3 and activating STAT3 in macrophages from patients with long-term cigarette smoking-related active pulmonary tuberculosis

Abstract

BackgroundCigarette smoking (CS) triggers an intense and harmful inflammatory response in lungs mediated by alveolar and blood macrophages, monocytes, and neutrophils and is closely associated with prevalence of tuberculosis (TB). The risk of death in patients with long-term cigarette smoking-related pulmonary tuberculosis (LCS-PTB) is approximately 4.5 times higher than those with nonsmoking pulmonary tuberculosis (N-PTB). However, the mechanisms underlying the harmful inflammatory responses in the setting of LCS-PTB have not been well documented.Methods28 cases LCS-PTB patients, 22 cases N-PTB patients and 20 cases healthy volunteers were enrolled in this study. Monocytes were isolated from peripheral blood mononuclear cells. Differentiated human MDM and U937 cell were prepared with M-CSF and PMA stimulation, respectively. The miR-196b-5p, STAT1, STAT3, STAT4, STAT5A, STAT5B, STAT6, SOCS1 and SOCS3 mRNA expression were detected by qRT-PCR. Western blot was performed according to SOCS1, SOCS3, and pSTAT3 expression. The mycobacterial uptake by MDMs from different groups of patients after Bacillus Calmette–Guérin (BCG) infection and agomir-196b-5p or antagomir-196b-5p transfection were used by flow cytometry analysis. Human IL-6, IL-10 and TNF-α levels on the plasma and cell culture supernatant samples were measured using ELISA. For dual-luciferase reporter assay, the SOCS3 3′-UTR segments, containing the binding elements of miR-196b-5p or its mutant versions were synthesized as sense and antisense linkers.ResultsIn this study, we found that IL-6, TNF-α production, SOCS3 mRNA expression were downregulated, while miR-196b-5p and STAT3 mRNA expression were upregulated in monocytes from LCS-PTB patients as compared to N-PTB patients. Meanwhile, we demonstrated that miR-196b-5p could target SOCS3 and activate STAT3 signaling pathway, which may possibly contribute to attenuation of BCG uptake and decrease in IL-6 and TNF-α production in macrophages.ConclusionsOur findings revealed that CS exposure regulates inflammatory responses in monocyte/macrophages from LCS-PTB patients via upregulating miR-196b-5p, and further understanding of the specific role of miR-196b-5p in inflammatory responses mightfacilitate elucidating the pathogenesis of LCS-PTB, thus leading to the development of new therapeutic strategies for PTB patients with long-term cigarette smoking.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1654-9) contains supplementary material, which is available to authorized users.

Phosphorylated STAT3 suppresses microRNA‐19b/1281 to aggravate lung injury in mice with type 2 diabetes mellitus‐associated pulmonary tuberculosis

“…Given to the increasing incidence of Mtb reactivation and the especially high recurrence and mortality rate in TB patients associated been witnessed in patients with PTB or with T2DM-PTB vs that in healthy individuals. 2,26 We then found that pSTAT3 expression was bacterial infection in lung. 30,31 For instance, miR-27b was found to suppress the secretion of pro-inflammatory factors and the nuclear factor-kappa B (NF-κB) signalling pathway to avoid an excessive inflammation during Mtb infection.…”

MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2

“…SOCS2 along with other members of SOCS family are regarded as importantly negative regulator of the JAK/STAT pathway 33 . Although STAT3 signaling might be more important than STAT5 in HCC progression and miR-196b could activate STAT3 by targeting SOCS2 in macrophages 34,35 , previous work showed that importance of JAK2/STAT5 signaling in liver metabolism, liver diseases, and HCC 36 . Hence, we…”

Unique inflammatory signature in haemophilic arthropathy: miRNA changes due to interaction between blood and fibroblast‐like synoviocytes

“…Interestingly, some of these miRNAs, such as miR‐146‐5p, 16,17 miR‐204‐3p, 18 miR‐130b‐3p, 19 miR‐25‐3p, 20 miR‐10b‐5p, 21 miR‐221‐5p, 22 miR‐4284 23 and miR‐3942‐5p 24 , have previously been described as being involved in regulating inflammation in RA, Sjögren's syndrome, lupus, familial Mediterranean fever, ankylosing spondylitis and Crohn's disease. Others have been described as playing a major role in inflammatory control, such as miR‐1246 25,26 in macrophage polarization, miR‐585‐5p 27 in oxidative stress through PARP1, miR‐34‐3p 28,29 in fibroblast proliferation and TNF‐α expression, miR‐196b‐5p 30 in SOCS3/STAT3 activation, miR‐146b‐5p in IL‐1α/IL‐6/IL‐8 control through the TLR4 pathway 31,32 and miR‐224 33 through the PTEN pathway. Many of these have been reported to play a role the pathogenesis of solid and haematologic tumours.…”