Differential Regulation of the Let-7 Family of MicroRNAs in CD4+ T Cells Alters IL-10 Expression

Abstract

MicroRNAs (miRNAs) are ∼22-nt small RNAs that are important regulators of mRNA turnover and translation. Recent studies have shown the importance of the miRNA pathway in HIV-1 infection, particularly in maintaining latency. Our initial in vitro studies demonstrated that HIV-1–infected HUT78 cells expressed significantly higher IL-10 levels compared with uninfected cultures. IL-10 plays an important role in the dysregulated cytotoxic T cell response to HIV-1, and in silico algorithms suggested that let-7 miRNAs target IL10 mRNA. In a time course experiment, we demonstrated that let-7 miRNAs fall rapidly following HIV-1 infection in HUT78 cells with concomitant rises in IL-10. To show a direct link between let-7 and IL-10, forced overexpression of let-7 miRNAs resulted in significantly reduced IL-10 levels, whereas inhibition of the function of these miRNAs increased IL-10. To demonstrate the relevance of these results, we focused our attention on CD4+ T cells from uninfected healthy controls, chronic HIV-1–infected patients, and long-term nonprogressors. We characterized miRNA changes in CD4+ T cells from these three groups and demonstrated that let-7 miRNAs were highly expressed in CD4+ T cells from healthy controls and let-7 miRNAs were significantly decreased in chronic HIV-1 infected compared with both healthy controls and long-term nonprogressors. We describe a novel mechanism whereby IL-10 levels can be potentially modulated by changes to let-7 miRNAs. In HIV-1 infection, the decrease in let-7 miRNAs may result in an increase in IL-10 from CD4+ T cells and provide the virus with an important survival advantage by manipulating the host immune response.

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

“…21,49,50 In light of our previous findings, 11 sPIF downregulates microRNA let-7 expression through PI3K/Akt signaling, also in a TLR4-dependent manner reducing neuronal death. Meanwhile, decreased let-7 levels lead to increased expression of IL10, a direct target of let-7-mediated inhibition 55,56 and a potent anti-inflammatory cytokine in neuroprotection. [57][58][59] Given the potent in vivo neuroprotective effects of sPIF, 10,11 we propose that the two pathways (PKA/PKC and PI3K/Akt) may work synergistically in sPIF-mediated neuroprotection.…”

Cross‐regulation between cytokine and microRNA pathways in T cells

“…One interesting example comes from the observation of decreased levels of let-7 during HIV-1 infection [71]. It remains speculative whether let-7 modulates IL-10 production in this setting, and if the generation of an immunosuppressive milieu confers a survival benefit for HIV-1 [71]. Another study has shown that in macrophages infected with Mycobacterium tuberculosis, let-7 is downregulated, which in turn promotes bacterial survival and suppresses responses [72].…”

“…Regarding the let-7 miRNA family, and as a side note, it is remarkable that pathogens that have coevolved with the mammalian immune system have developed strategies that interfere with the host's miRNAs in order to modulate the immune response and cytokine production. One interesting example comes from the observation of decreased levels of let-7 during HIV-1 infection [71]. It remains speculative whether let-7 modulates IL-10 production in this setting, and if the generation of an immunosuppressive milieu confers a survival benefit for HIV-1 [71].…”

Chronic Administration of Δ 9 -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

“…These findings also suggest that the protective effects of cannabinoids may also be mediated by similar regulatory factors/mechanisms (epigenetic) that need to be further investigated and identified, especially as they relate to HIV infection. For instance, several in vitro studies have shown altered miRNA expression in response to HIV infection (30)(31)(32)(33)(34), and recent miRNA profiling studies performed on brain (35) and plasma samples (36) provide strong evidence of their dysregulation during SIV infection. In addition, we recently reported miR-190b to be significantly upregulated in the intestine at all stages of SIV infection (37) and that viral replication rather than infection-related inflammatory responses induced miR-190b upregulation (37).…”