Posttranscriptional Regulation of Il10 Gene Expression Allows Natural Killer Cells to Express Immunoregulatory Function

Abstract

Natural killer (NK) cells play a well-recognized role in early pathogen containment and in shaping acquired cell-mediated immunity. However, indirect evidence in humans and experimental models has suggested that NK cells also play negative regulatory roles during chronic disease. To formally test this hypothesis, we employed a well-defined experimental model of visceral leishmaniasis. Our data demonstrated that NKp46(+)CD49b(+)CD3(-) NK cells were recruited to the spleen and into hepatic granulomas, where they inhibited host protective immunity in an interleukin-10 (IL-10)-dependent manner. Although IL-10 mRNA could be detected in activated NK cells 24 hr after infection, the inhibitory function of NK cells was only acquired later during infection, coincident with increased IL-10 mRNA stability and an enhanced capacity to secrete IL-10 protein. Our data support a growing body of literature that implicates NK cells as negative regulators of cell-mediated immunity and suggest that NK cells, like CD4(+) T helper 1 cells, may acquire immunoregulatory functions as a consequence of extensive activation.

Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a

“…It seems plausible that 3 regulatory mechanisms like transcriptional regulation, ARE mediated 3Ј UTR regulation, and hsa-miR-106a mediated 3Ј UTR regulation may critically regulate IL-10 expression. In fact, recently, it has been shown that inhibitory function of NKp46 ϩ CD49b ϩ CD3 Ϫ NK cells recruited in the hepatic granulomas in experimental model of visceral leishmaniasis was correlated with high IL-10 production as a result of increased stability of IL10 mRNA (28). It is very likely that hsa-miR-106a mediated posttranscriptional control could potentially be involved in fine tuning the critical level of IL-10 expression in a context-dependent manner, and hence dictates the outcome of immune response to specific external stimuli.…”

The Interactions of Multiple Cytokines Control NK Cell Maturation

“…A striking example of the difference between short-and long-term cultures is IL-10 expression. Whereas Il10 mRNA is rapidly induced in activated NK cells, IL-10 is not secreted until much later in an immune response (54).…”

Novel Highly Sensitive IL-10–β-Lactamase Reporter Mouse Reveals Cells of the Innate Immune System as a Substantial Source of IL-10 In Vivo

“…It seems that, at least in the steady state, the Il10-39 UTR mediates Il10 mRNA instability more profoundly in B cells than in macrophages and thus confers stronger suppression of IL-10 protein production in the former cell type. Recently, posttranscriptional regulation of Il10 gene expression has been shown to control specifically IL-10 secretion by NK cells (47). Furthermore, it has been shown that, compared with normal melanocytes, the melanoma cell line MNT1 exhibits reduced cytoplasmic levels of AU-rich element binding factor 1, an AU-rich element binding protein that mediate mRNA instability, resulting in IL-10 overexpression and tumor escape (40).…”