Interleukin-33 promotes type 1 cytokine expression via p38 MAPK in human natural killer cells

This study tests the hypothesis that activation of mitogen-activated protein kinase (MAPK) by physiologically-relevant concentrations of interleukin-33 (IL-33) contributes to enhanced cytokine expression by IL-12 stimulated human natural killer (NK) cells. While IL-33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL-12 to provoke interferon-gamma (IFN-{gamma}). We show that picogram concentrations of IL-12 and IL-33 are sufficient to promote robust secretion of IFN-{gamma} by human NK cells that greatly exceeds responses to either cytokine alone. Nanogram doses of IL-33, potentially consistent with levels in tissue microenvironments, synergize with IL-12 to induce secretion of additional cytokines, including tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-33-induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN-{gamma} and TNF in response to IL-12. Mechanistically, IL-33-induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers ADAM17-mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL-12 in the presence of IL-33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/777847v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@c1f7c9org.highwire.dtl.DTLVardef@72d47dorg.highwire.dtl.DTLVardef@dc84d4org.highwire.dtl.DTLVardef@194b42f_HPS_FORMAT_FIGEXP M_FIG C_FIG