Apoptotic cells inhibit LPS-induced cytokine and chemokine production and IFN responses in macrophages.
Apoptosis is a critical process in tissue homeostasis and results in immediate removal of the dying cell by professional phagocytes such as macrophages and dendritic cells. Phagocytosis of apoptotic cells actively suppresses production of proinflammatory growth factors and cytokines. Impaired phagocytosis of apoptotic cells has been implicated in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study we found that, in addition to suppressing lipopolysaccharide (LPS)-induced production of TNF-alpha and IL-6, phagocytosis of apoptotic cells by macrophages suppressed production of the chemokine CXCL10 that is activated by LPS-induced autocrine-acting type I IFNs. Inhibition of cytokine and chemokine production was not universally affected because LPS-induced production of IL-10 and IL-8 was not significantly affected. Apoptotic cells had minimal effects on LPS-induced activation of NF-kappaB and MAPKs, but induced expression of SOCS proteins and substantially suppressed induction of CXCL10 expression by IFN-alpha. In addition to suppressing LPS responses, apoptotic cells inhibited macrophage responses to another major macrophage activator IFN-gamma by attenuating IFN-gamma-induced STAT1 activation and downstream gene expression. These results identify suppressive effects of apoptotic cells on signal transduction, and extend our understanding of the anti-inflammatory effects of apoptotic cells to include suppression of Jak-STAT signaling.
Tassiulas
Ioannis
I
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.
Park-Min
Kyung-Hyun
KH
Hu
Yang
Y
Kellerman
Lisa
L
Mevorach
Dror
D
Ivashkiv
Lionel B
LB
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019898:Autocrine Communication / Q000187:drug effects; D054357:Chemokine CXCL10; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000637:transplantation; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; C508609:IL10 protein, human; C508600:IL6 protein, human; D007370:Interferon Type I; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D003907:Dexamethasone; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma