Abstract
Persistent activation and inflammation impair immune response and trigger disease progression in HIV infection. Emerging evidence supports the supposition that excessive production of interferon-inducible protein 10 (IP-10), a critical inflammatory cytokine, leads to immune dysfunction and disease progression in HIV infection. In this study, we sought to elucidate the cause of the upregulated production of IP-10 in HIV infection and explore the underlying mechanisms. Bolstering miR-21 levels using mimics resulted in the obvious suppression of lipopolysaccharide (LPS)-induced IP-10 in monocyte leukemia cells THP-1 and vice versa. The analysis of the primary monocytes of HIV patients revealed significantly less miR-21 than in healthy controls; this was opposite to the tendency of IP-10 levels in plasma. The secretion of IP-10 due to LPS stimulation was not affected by miR-21 modulation in the differentiated THP-1 macrophages (THP-1-MA). We found a novel switch, IFN-stimulated gene 15 (ISG15), which triggers the expression of IP-10 and is significantly upregulated during the differentiation of THP-1 into THP-1-MA. The inhibition of ISG15 can restore the regulation of IP-10 by miR-21. In summary, IP-10 expression in monocytes is regulated by miR-21, whereas in macrophages, this fine-tuning is attenuated by the enhanced expression of ISG15. This study paves the way to a comprehensive understanding of the molecular regulatory mechanism of IP-10, a key point in immune intervention strategy.
Highlights
The deterioration of the gut epithelium and enlarged microbial translocation triggered by the rapid depletion of gastrointestinal CD4+ T cells leads to a persistent, systemic activation, and inflammation of HIV infections [1, 2]
inducible protein 10 (IP-10) is a pro-inflammatory chemokine expressed within a variety of cell types with pleiotropic function [40] and plays a pivotal role in regulating monocyte-mediated inflammatory responses as well as enhanced immune activation [41], thereby facilitating the disease progression of HIV [6, 10, 12, 13]
Previous studies performed on porcine kidney 15 cell lines and peritoneal macrophages from Sprague Dawley rats have showed that IP-10 was targeted by miR-21 [42, 43]
Summary
The deterioration of the gut epithelium and enlarged microbial translocation triggered by the rapid depletion of gastrointestinal CD4+ T cells leads to a persistent, systemic activation, and inflammation of HIV infections [1, 2]. In HIV infection, elevated blood levels of IP-10 are associated with rapid disease progression and persistent immune activation [6, 10,11,12]. Previous studies found that IP-10 decreased the function of T cells [13] and NK cells [14] and stimulated HIV replication [15]. This indicates that the regulation of IP-10 expression in HIV infection influences the delay of inflammation, slowing down disease progression. The factors triggering the significant upregulation of IP-10, especially at a post-transcriptional level in HIV infection have not been clearly elucidated
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