Pro- and Antiinflammatory Cytokine Signaling: Reciprocal Antagonism Regulates Interferon-gamma Production by Human Natural Killer Cells

Jianhua Yu, Min Wei, Brian Becknell, Rossana Trotta, Shujun Liu, Zachary Boyd, Michael S. Jaung, Bradley W. Blaser, Jin Sun, Don M. Benson, Hsiaoyin Mao, Akihiko Yokohama, Darshna Bhatt, Lei Shen, Ramana Davuluri, Michael Weinstein, Guido Marcucci, Michael A. Caligiuri*

*Corresponding author for this work

Research output: Contribution to journalArticle

136 Scopus citations

Abstract

Activated monocytes produce proinflammatory cytokines (monokines) such as interleukin (IL)-12, IL-15, and IL-18 for induction of interferon-γ (IFN-γ) by natural killer (NK) cells. NK cells provide the antiinflammatory cytokine transforming growth factor (TGF)-β, an autocrine/negative regulator of IFN-γ. The ability of one signaling pathway to prevail over the other is likely important in controlling IFN-γ for the purposes of infection and autoimmunity, but the molecular mechanism(s) of how this counterregulation occurs is unknown. Here we show that in isolated human NK cells, proinflammatory monokines antagonize antiinflammatory TGF-β signaling by downregulating the expression of the TGF-β type II receptor, and its signaling intermediates SMAD2 and SMAD3. In contrast, TGF-β utilizes SMAD2, SMAD3, and SMAD4 to suppress IFN-γ and T-BET, a positive regulator of IFN-γ. Indeed, activated NK cells from Smad3-/- mice produce more IFN-γ in vivo than NK cells from wild-type mice. Collectively, our data suggest that pro- and antiinflammatory cytokine signaling reciprocally antagonize each other in an effort to prevail in the regulation of NK cell IFN-γ production.

Original languageEnglish (US)
Pages (from-to)575-590
Number of pages16
JournalImmunity
Volume24
Issue number5
DOIs
StatePublished - May 1 2006

Keywords

  • CELLIMMUNO
  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Yu, J., Wei, M., Becknell, B., Trotta, R., Liu, S., Boyd, Z., Jaung, M. S., Blaser, B. W., Sun, J., Benson, D. M., Mao, H., Yokohama, A., Bhatt, D., Shen, L., Davuluri, R., Weinstein, M., Marcucci, G., & Caligiuri, M. A. (2006). Pro- and Antiinflammatory Cytokine Signaling: Reciprocal Antagonism Regulates Interferon-gamma Production by Human Natural Killer Cells. Immunity, 24(5), 575-590. https://doi.org/10.1016/j.immuni.2006.03.016