NK Cell IL-10 Production Requires IL-15 and IL-10 Driven STAT3 Activation

Abstract

Natural killer (NK) cells can produce IFNγ or IL-10 to regulate inflammation and immune responses but the factors driving NK cell IL-10 secretion are poorly-defined. Here, we identified NK cell-intrinsic STAT3 activation as vital for IL-10 production during both systemic Listeria monocytogenes (Lm) infection and following IL-15 cytokine/receptor complex (IL15C) treatment for experimental cerebral malaria (ECM). In both contexts, conditional Stat3 deficiency in NK cells abrogated production of IL-10. Initial NK cell STAT3 phosphorylation was driven by IL-15. During Lm infection, this required capture or presentation of IL-15 by NK cell IL-15Rα. Persistent STAT3 activation was required to drive measurable IL-10 secretion and required NK cell expression of IL-10Rα. Survival-promoting effects of IL-15C treatment in ECM were dependent on NK cell Stat3 while NK cell-intrinsic deficiency for Stat3, Il15ra, or Il10ra abrogated NK cell IL-10 production and increased resistance against Lm. NK cell Stat3 deficiency did not impact production of IFNγ, indicating the STAT3 activation initiated by IL-15 and amplified by IL-10 selectively drives the production of anti-inflammatory IL-10 by responding NK cells.

IL-10-Producing ILCs: Molecular Mechanisms and Disease Relevance

“…It has been determined that STAT3 activation is closely related to the production of IL-10 (51-53). Whether IL-15C treatment or during systemic Lm infection, NKSTAT3mice do not produce IL-10 efficiently, and there is ample evidence that serum IL-10 levels in NKSTAT3mice are similar to those in B6.IL-10 -/mice despite Lm infection (35). Similarly, in NK-tumor cocultures, low-dose GPB730 (selective STAT3 inhibitor) pretreatment of NK cells can also inhibit the production of IL-10 (15).…”

“…Among them, IL-15 has attracted much attention due to its therapeutic potential in cancer ( 33 , 34 ). Recently, in murine models of Lm infection and experimental cerebral malaria (ILM), it was reported that IL-15 cytokine/receptor complex (IL15C) produces IL-10 by driving STAT3 phosphorylation in NK cells ( 26 , 35 ) ( Figure 1 ). Specifically, STAT3 signal transduction and NK cells IL-10 production are detrimental to host innate resistance to Lm, but may contribute to the survival of cerebral malaria models.…”

Reliability and suitability of physiological exercise response and recovery markers

“…Thus, the anti-inflammatory cytokine, IL-1RA, seems to be a reliable and suitable marker which reflect the physiological exercise response and recovery processes in athletes’ during endurance exercises. IL-10 is primarily expressed by monocytes and represents an anti-inflammatory cytokine, while IL-15 is a regulator of the activity of T cells and natural killer cells 26 . Limitations in the methodological analysis of IL-10 and IL-15 are suggested to be the reason for the weak reliabilities within these cytokines.…”

Reply to: “A spotlight on natural killer cells in primary biliary cholangitis”

“…We agree with Dr Hydes and Prof. Khakoo on the relevance of NK cells in bridging innate with adaptive immunity in PBC, with one characteristic being enhanced interferon (IFN)-c, other than IL-10, production. 4,5 In particular, NK cell cytotoxicity against biliary epithelial cells (BECs) is initiated only after toll-like receptor (TLR) 3-mediated NK stimulation and TLR4-mediated monocyte stimulation. This function is regulated by a large family of inhibitory NK cell receptors, including killer-cell immunoglobulin-like receptors and C-lectin type molecules, which recognize major histocompatibility complex (MHC) class I present on autologous cells.…”