Activation-induced apoptosis in human macrophages: Developmental regulation of a novel cell death pathway by macrophage colony-stimulating factor and interferon γ

David H. Munn, Arthur C. Beall, Danny Song, Robert W. Wrenn, Douglas C. Throckmorton

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

Activated macrophages (Mφs) are important participants in host defense, but their uncontrolled activation leads rapidly to septic shock and death. One mechanism for regulating other dangerous cells in the immune system is programmed cell death, or apoptosis. Monocytes are known to undergo spontaneous apoptosis upon leaving the circulation unless provided with specific survival signals, but mature tissue Mφs are more robust cells, and it was not dear that they could be similarly regulated by apoptosis. We now show that during differentiation monocytes rapidly lose their sensitivity to apoptosis triggered by passive cytokine withdrawal, but they may retain a novel pathway which initiates apoptosis after activation with specific stimuli (zymosan and phorbol esters). Sensitivity to activation-induced apoptosis was developmentally determined, being downregulated by the maturation-promoting cytokine macrophage colony-stimulating factor but stably upregulated by even transient exposure to the proinflammatory cytokine interferon γ (IFN-γ). Apoptosis began within 2--4 h of activation, occurred in <95% of susceptible cells, and in mixed cocultures sdectively affected only those M-bs with a history of IFN-γ priming. Consistent with a possible role for protein kinase C in the signaling pathway leading to cell death, the kinase inhibitor staurosporine was protective against both phorbol ester- and zymosaninduced apoptosis. Our studies describe a novel form of activation-induced Mφk apoptosis which is developmentally regulated by two physiologically relevant cytokines. We speculate that apoptosis may serve to restrict the destructive potential of inflammatory Mφs.

Original languageEnglish (US)
Pages (from-to)127-136
Number of pages10
JournalJournal of Experimental Medicine
Volume181
Issue number1
DOIs
StatePublished - Jan 1 1995

Fingerprint

Macrophage Colony-Stimulating Factor
Interferons
Cell Death
Macrophages
Apoptosis
Cytokines
Phorbol Esters
Monocytes
Zymosan
Staurosporine
Septic Shock
Coculture Techniques
Protein Kinase C
Immune System
Phosphotransferases
Down-Regulation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Activation-induced apoptosis in human macrophages : Developmental regulation of a novel cell death pathway by macrophage colony-stimulating factor and interferon γ. / Munn, David H.; Beall, Arthur C.; Song, Danny; Wrenn, Robert W.; Throckmorton, Douglas C.

In: Journal of Experimental Medicine, Vol. 181, No. 1, 01.01.1995, p. 127-136.

Research output: Contribution to journalArticle

@article{49d407d430274ce4a2a061efc158d315,
title = "Activation-induced apoptosis in human macrophages: Developmental regulation of a novel cell death pathway by macrophage colony-stimulating factor and interferon γ",
abstract = "Activated macrophages (Mφs) are important participants in host defense, but their uncontrolled activation leads rapidly to septic shock and death. One mechanism for regulating other dangerous cells in the immune system is programmed cell death, or apoptosis. Monocytes are known to undergo spontaneous apoptosis upon leaving the circulation unless provided with specific survival signals, but mature tissue Mφs are more robust cells, and it was not dear that they could be similarly regulated by apoptosis. We now show that during differentiation monocytes rapidly lose their sensitivity to apoptosis triggered by passive cytokine withdrawal, but they may retain a novel pathway which initiates apoptosis after activation with specific stimuli (zymosan and phorbol esters). Sensitivity to activation-induced apoptosis was developmentally determined, being downregulated by the maturation-promoting cytokine macrophage colony-stimulating factor but stably upregulated by even transient exposure to the proinflammatory cytokine interferon γ (IFN-γ). Apoptosis began within 2--4 h of activation, occurred in <95{\%} of susceptible cells, and in mixed cocultures sdectively affected only those M-bs with a history of IFN-γ priming. Consistent with a possible role for protein kinase C in the signaling pathway leading to cell death, the kinase inhibitor staurosporine was protective against both phorbol ester- and zymosaninduced apoptosis. Our studies describe a novel form of activation-induced Mφk apoptosis which is developmentally regulated by two physiologically relevant cytokines. We speculate that apoptosis may serve to restrict the destructive potential of inflammatory Mφs.",
author = "Munn, {David H.} and Beall, {Arthur C.} and Danny Song and Wrenn, {Robert W.} and Throckmorton, {Douglas C.}",
year = "1995",
month = "1",
day = "1",
doi = "10.1084/jem.181.1.127",
language = "English (US)",
volume = "181",
pages = "127--136",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "1",

}

TY - JOUR

T1 - Activation-induced apoptosis in human macrophages

T2 - Developmental regulation of a novel cell death pathway by macrophage colony-stimulating factor and interferon γ

AU - Munn, David H.

AU - Beall, Arthur C.

AU - Song, Danny

AU - Wrenn, Robert W.

AU - Throckmorton, Douglas C.

PY - 1995/1/1

Y1 - 1995/1/1

N2 - Activated macrophages (Mφs) are important participants in host defense, but their uncontrolled activation leads rapidly to septic shock and death. One mechanism for regulating other dangerous cells in the immune system is programmed cell death, or apoptosis. Monocytes are known to undergo spontaneous apoptosis upon leaving the circulation unless provided with specific survival signals, but mature tissue Mφs are more robust cells, and it was not dear that they could be similarly regulated by apoptosis. We now show that during differentiation monocytes rapidly lose their sensitivity to apoptosis triggered by passive cytokine withdrawal, but they may retain a novel pathway which initiates apoptosis after activation with specific stimuli (zymosan and phorbol esters). Sensitivity to activation-induced apoptosis was developmentally determined, being downregulated by the maturation-promoting cytokine macrophage colony-stimulating factor but stably upregulated by even transient exposure to the proinflammatory cytokine interferon γ (IFN-γ). Apoptosis began within 2--4 h of activation, occurred in <95% of susceptible cells, and in mixed cocultures sdectively affected only those M-bs with a history of IFN-γ priming. Consistent with a possible role for protein kinase C in the signaling pathway leading to cell death, the kinase inhibitor staurosporine was protective against both phorbol ester- and zymosaninduced apoptosis. Our studies describe a novel form of activation-induced Mφk apoptosis which is developmentally regulated by two physiologically relevant cytokines. We speculate that apoptosis may serve to restrict the destructive potential of inflammatory Mφs.

AB - Activated macrophages (Mφs) are important participants in host defense, but their uncontrolled activation leads rapidly to septic shock and death. One mechanism for regulating other dangerous cells in the immune system is programmed cell death, or apoptosis. Monocytes are known to undergo spontaneous apoptosis upon leaving the circulation unless provided with specific survival signals, but mature tissue Mφs are more robust cells, and it was not dear that they could be similarly regulated by apoptosis. We now show that during differentiation monocytes rapidly lose their sensitivity to apoptosis triggered by passive cytokine withdrawal, but they may retain a novel pathway which initiates apoptosis after activation with specific stimuli (zymosan and phorbol esters). Sensitivity to activation-induced apoptosis was developmentally determined, being downregulated by the maturation-promoting cytokine macrophage colony-stimulating factor but stably upregulated by even transient exposure to the proinflammatory cytokine interferon γ (IFN-γ). Apoptosis began within 2--4 h of activation, occurred in <95% of susceptible cells, and in mixed cocultures sdectively affected only those M-bs with a history of IFN-γ priming. Consistent with a possible role for protein kinase C in the signaling pathway leading to cell death, the kinase inhibitor staurosporine was protective against both phorbol ester- and zymosaninduced apoptosis. Our studies describe a novel form of activation-induced Mφk apoptosis which is developmentally regulated by two physiologically relevant cytokines. We speculate that apoptosis may serve to restrict the destructive potential of inflammatory Mφs.

UR - http://www.scopus.com/inward/record.url?scp=0028955622&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028955622&partnerID=8YFLogxK

U2 - 10.1084/jem.181.1.127

DO - 10.1084/jem.181.1.127

M3 - Article

C2 - 7806999

AN - SCOPUS:0028955622

VL - 181

SP - 127

EP - 136

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 1

ER -