IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

David E. Ochayon, Ayad Ali, Pablo C. Alarcon, Durga Krishnamurthy, Leah C. Kottyan, Michael T. Borchers, Stephen N. Waggoner

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL-33 contributes to enhanced cytokine expression by IL-12 stimulated human 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 IFN-γ. We show that picogram concentrations of IL-12 and IL-33 are sufficient to promote robust secretion of IFN-γ by human NK cells that greatly exceeds resposes 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 TNF and GM-CSF. IL-33-induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN-γ and TNF in response to IL-12. Mechanistically, IL-33-induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (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.

Original languageEnglish
Pages (from-to)663-671
Number of pages9
JournalJournal of Leukocyte Biology
Issue number4
StatePublished - 1 Apr 2020
Externally publishedYes


  • GM-CSF
  • IL-12
  • NK
  • TNF
  • innate lymphoid cell
  • synergy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology


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