Abstract
Interleukin-37 (IL-37) is a recently identified cytokine with potent antiinflammatory and immunosuppressive functions. The objective of this study was to compare levels of IL-37 mRNA in immunological subgroups of chronic human immunodeficiency virus-1 (HIV-1)-infected individuals and noninfected controls, to determine IL-37's association with biomarkers of inflammation and reservoir size. This was a cross-sectional study. The HIV-1-infected patients were categorized in three subgroups depending on their combination antiretroviral therapy (cART) treatment status and CD4(+) T-cell count. Quantitative RT-PCR was used for the detection of IL-37 mRNA and HIV-1 DNA in peripheral blood mononuclear cells (PBMCs). Biomarkers in plasma were quantified by enzyme-linked immunosorbent assay (ELISA), whereas T-cell activation was determined by flow cytometry. Lastly, lipopolysaccharide (LPS) stimulations of patients PBMCs were carried out to determine differences in IL-37 mRNA response between the subgroups. Sixty HIV-1-infected patients and 20 noninfected controls were included in the study. Steady-state IL-37 mRNA levels in PBMCs were significantly higher in HIV-1-infected individuals compared with noninfected controls: 2.4-fold (p ≤ 0.01) cART-naïve subjects; 3.9-fold (p ≤ 0.0001) inadequate immunological responders; and 4.0-fold (p ≤ 0.0001) in immunological responders compared with non-infected controls. Additionally, levels of the monocyte inflammatory marker sCD14 correlated with IL-37 mRNA (p = 0.03), whereas there was no association with T-cell activation. Finally, we observed a significant correlation between total viral HIV-1 DNA and IL-37 mRNA in PBMCs (p < 0.0001). Collectively, our data shows that the level of IL-37 mRNA is affected by chronic HIV-1-infection. A relationship with the activation of the monocyte compartment is suggested by the correlation with sCD14 and, interestingly, IL-37 could be related to the size of the total viral HIV-1 reservoir.
Highlights
The newly described interleukin-37 has emerged as an important part of the antiinflammatory system affecting both innate and adaptive immunity
Though the relative induction of IL-37 mRNA did not differ between groups, the absolute increase in IL-37 mRNA was higher in the human immunodeficiency virus1 (HIV-1)-infected groups (Figure 3)
That the observed increased expression of IL-37 could play a regulatory role in HIV-1 by limiting inand immunological responders (IIRs) compared with noninfected controls (p ≤ 0.001; p ≤ 0.05), with the highest levels in the combination antiretroviral therapy (cART)-naïve group
Summary
The newly described interleukin-37 has emerged as an important part of the antiinflammatory system affecting both innate and adaptive immunity. We know that within the interleukin-1 (IL-1) family, the proinflammatory members are tightly regulated to avoid excessive inflammation. Examples of this include the potent blocking of IL-1α and IL1-β by IL-1 receptor antagonist [1], IL-18 binding protein’s capacity to neutralize IL-18 [2] and IL-36 receptor antagonist’s ability to reduce IL-36 activity [3]. Five transcript variants (IL-37a–e) have been described with the largest, IL-37b containing five of the six exons [6,7,8,9,10]. In PBMCs, IL-37 protein is primarily expressed in monocytic cells [11]
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