Glucocorticoid-induced tumor necrosis factor receptor negatively regulates activation of human primary natural killer (NK) cells by blocking proliferative signals and increasing NK cell apoptosis

Baoying Liu, Zhuqing Li, Sankaranarayana P. Mahesh, Seth Pantanelli, Frank S. Hwang, Willie O. Siu, Robert B. Nussenblatt

Research output: Contribution to journalArticle

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Abstract

Glucocorticoid-induced tumor necrosis factor receptor (GITR), found constitutively expressed on human primary natural killer (NK) cells at low levels was up-regulated upon stimulation by either Toll-like receptor ligand or NK cell growth factor, interleukin (IL)-15. cDNA microarray analysis showed that engagement of GITR primarily suppressed the activation of NF-KB pathway of NK cells and up-regulated anti-inflammatory genes heme oxygenase-1 and IL-10. Further analysis revealed that GITR activation suppressed NK cell proliferation in response to IL-15. GITR activation also suppressed proinflammatory cytokine secretion and increased NK cell apoptosis. GITR activation resulted in blocked phosphorylation of Stat5 and Akt, which may have contributed to the observed antiproliferative effect of GITR on NK cells. Increased apoptosis was independent of the Fas-FasL pathway, but Bcl-XL and phospho-Bad protein expressions were diminished, suggesting involvement of the mitochondrial apoptosis pathway. The results suggest that although GITR is an activation marker for NK cells similar to that for T cells, GITR serves as a negative regulator for NK cell activation. Our studies demonstrate a novel physiological role of GITR on NK cells.

Original languageEnglish (US)
Pages (from-to)8202-8210
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number13
DOIs
StatePublished - Mar 28 2008

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Tumor Necrosis Factor Receptors
Natural Killer Cells
Glucocorticoids
Chemical activation
Apoptosis
Interleukin-15
bcl-Associated Death Protein
Phosphorylation
Heme Oxygenase-1
T-cells
Toll-Like Receptors
Cell proliferation
Cell growth
Microarray Analysis
Microarrays
Oligonucleotide Array Sequence Analysis
Interleukin-10
Intercellular Signaling Peptides and Proteins
Anti-Inflammatory Agents
Complementary DNA

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Liu, Baoying ; Li, Zhuqing ; Mahesh, Sankaranarayana P. ; Pantanelli, Seth ; Hwang, Frank S. ; Siu, Willie O. ; Nussenblatt, Robert B. / Glucocorticoid-induced tumor necrosis factor receptor negatively regulates activation of human primary natural killer (NK) cells by blocking proliferative signals and increasing NK cell apoptosis. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 13. pp. 8202-8210.
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Glucocorticoid-induced tumor necrosis factor receptor negatively regulates activation of human primary natural killer (NK) cells by blocking proliferative signals and increasing NK cell apoptosis. / Liu, Baoying; Li, Zhuqing; Mahesh, Sankaranarayana P.; Pantanelli, Seth; Hwang, Frank S.; Siu, Willie O.; Nussenblatt, Robert B.

In: Journal of Biological Chemistry, Vol. 283, No. 13, 28.03.2008, p. 8202-8210.

Research output: Contribution to journalArticle

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AU - Nussenblatt, Robert B.

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N2 - Glucocorticoid-induced tumor necrosis factor receptor (GITR), found constitutively expressed on human primary natural killer (NK) cells at low levels was up-regulated upon stimulation by either Toll-like receptor ligand or NK cell growth factor, interleukin (IL)-15. cDNA microarray analysis showed that engagement of GITR primarily suppressed the activation of NF-KB pathway of NK cells and up-regulated anti-inflammatory genes heme oxygenase-1 and IL-10. Further analysis revealed that GITR activation suppressed NK cell proliferation in response to IL-15. GITR activation also suppressed proinflammatory cytokine secretion and increased NK cell apoptosis. GITR activation resulted in blocked phosphorylation of Stat5 and Akt, which may have contributed to the observed antiproliferative effect of GITR on NK cells. Increased apoptosis was independent of the Fas-FasL pathway, but Bcl-XL and phospho-Bad protein expressions were diminished, suggesting involvement of the mitochondrial apoptosis pathway. The results suggest that although GITR is an activation marker for NK cells similar to that for T cells, GITR serves as a negative regulator for NK cell activation. Our studies demonstrate a novel physiological role of GITR on NK cells.

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