Initial cytokine exposure determines function of macrophages and renders them unresponsive to other cytokines

L P Erwig, D C Kluth, Garry Michael Walsh, A J Rees

Research output: Contribution to journalArticle

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Abstract

The functional properties of infiltrating macrophages (M phi) must be tightly regulated to facilitate appropriate responses to complex conditions in an inflammatory focus. This study was designed to ascertain whether uncommitted M phi that have been exposed to combinations of cytokines with opposing functions develop properties dictated by one cytokine or by cytokine mixtures. Uncommitted rat bone marrow-derived M phi (BMDMs) were incubated with IFN-gamma, TNF-alpha, TGF-beta, IL-4, IL-6, and IL-10 alone or sequentially in combinations. After 48 h, function was assessed by nitric oxide (NO) generation, uptake of apoptotic neutrophils, and beta-glucuronidase expression. IFN-gamma followed 4 h later by TNF-induced NO generation. The pretreatment of BMDMs before IFN-gamma priming with TNF, TGF-beta, and IL-4 suppressed NO generation by 87%, 92%, and 85%, respectively; IL-10 had no effect. The same cytokines administered at 4 h after IFN priming had no effect on NO generation. The uptake of apoptotic polymorphonuclear leukocytes was augmented by TNF (40% vs 29% controls; p < 0.05) and decreased by IFN-gamma, IL-10, and IL-4. The TNF response was unaffected by subsequent treatment with IFN-gamma, IL-4, or IL-10. Similarly, the decreased polymorphonuclear leukocyte uptake induced by IFN-gamma, IL-4, or IL-10 was unaffected by the subsequent addition of TNF. beta-glucuronidase expression was increased by TGF-beta and decreased by IFN-gamma, These responses were not modified by cytokines with the opposing function. Thus, the functional response of BMDMs to complex mixtures of cytokines was determined by the first cytokine to which they were exposed. Once activated, BMDMs become unresponsive to alternative activating signals, a finding which has obvious implications for M phi function in vivo.

Original languageEnglish
Pages (from-to)1983-1988
Number of pages6
JournalThe Journal of Immunology
Volume161
Issue number4
Publication statusPublished - 15 Aug 1998

Keywords

  • GROWTH-FACTOR-BETA
  • NITRIC-OXIDE SYNTHASE
  • NECROSIS-FACTOR-ALPHA
  • ACTIVATED MACROPHAGE
  • VITRONECTIN RECEPTOR
  • MOUSE MACROPHAGES
  • INTERFERON-GAMMA
  • TNF-ALPHA
  • IFN-GAMMA
  • CELL

Cite this

Initial cytokine exposure determines function of macrophages and renders them unresponsive to other cytokines. / Erwig, L P ; Kluth, D C ; Walsh, Garry Michael; Rees, A J .

In: The Journal of Immunology, Vol. 161, No. 4, 15.08.1998, p. 1983-1988.

Research output: Contribution to journalArticle

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abstract = "The functional properties of infiltrating macrophages (M phi) must be tightly regulated to facilitate appropriate responses to complex conditions in an inflammatory focus. This study was designed to ascertain whether uncommitted M phi that have been exposed to combinations of cytokines with opposing functions develop properties dictated by one cytokine or by cytokine mixtures. Uncommitted rat bone marrow-derived M phi (BMDMs) were incubated with IFN-gamma, TNF-alpha, TGF-beta, IL-4, IL-6, and IL-10 alone or sequentially in combinations. After 48 h, function was assessed by nitric oxide (NO) generation, uptake of apoptotic neutrophils, and beta-glucuronidase expression. IFN-gamma followed 4 h later by TNF-induced NO generation. The pretreatment of BMDMs before IFN-gamma priming with TNF, TGF-beta, and IL-4 suppressed NO generation by 87{\%}, 92{\%}, and 85{\%}, respectively; IL-10 had no effect. The same cytokines administered at 4 h after IFN priming had no effect on NO generation. The uptake of apoptotic polymorphonuclear leukocytes was augmented by TNF (40{\%} vs 29{\%} controls; p < 0.05) and decreased by IFN-gamma, IL-10, and IL-4. The TNF response was unaffected by subsequent treatment with IFN-gamma, IL-4, or IL-10. Similarly, the decreased polymorphonuclear leukocyte uptake induced by IFN-gamma, IL-4, or IL-10 was unaffected by the subsequent addition of TNF. beta-glucuronidase expression was increased by TGF-beta and decreased by IFN-gamma, These responses were not modified by cytokines with the opposing function. Thus, the functional response of BMDMs to complex mixtures of cytokines was determined by the first cytokine to which they were exposed. Once activated, BMDMs become unresponsive to alternative activating signals, a finding which has obvious implications for M phi function in vivo.",
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T1 - Initial cytokine exposure determines function of macrophages and renders them unresponsive to other cytokines

AU - Erwig, L P

AU - Kluth, D C

AU - Walsh, Garry Michael

AU - Rees, A J

PY - 1998/8/15

Y1 - 1998/8/15

N2 - The functional properties of infiltrating macrophages (M phi) must be tightly regulated to facilitate appropriate responses to complex conditions in an inflammatory focus. This study was designed to ascertain whether uncommitted M phi that have been exposed to combinations of cytokines with opposing functions develop properties dictated by one cytokine or by cytokine mixtures. Uncommitted rat bone marrow-derived M phi (BMDMs) were incubated with IFN-gamma, TNF-alpha, TGF-beta, IL-4, IL-6, and IL-10 alone or sequentially in combinations. After 48 h, function was assessed by nitric oxide (NO) generation, uptake of apoptotic neutrophils, and beta-glucuronidase expression. IFN-gamma followed 4 h later by TNF-induced NO generation. The pretreatment of BMDMs before IFN-gamma priming with TNF, TGF-beta, and IL-4 suppressed NO generation by 87%, 92%, and 85%, respectively; IL-10 had no effect. The same cytokines administered at 4 h after IFN priming had no effect on NO generation. The uptake of apoptotic polymorphonuclear leukocytes was augmented by TNF (40% vs 29% controls; p < 0.05) and decreased by IFN-gamma, IL-10, and IL-4. The TNF response was unaffected by subsequent treatment with IFN-gamma, IL-4, or IL-10. Similarly, the decreased polymorphonuclear leukocyte uptake induced by IFN-gamma, IL-4, or IL-10 was unaffected by the subsequent addition of TNF. beta-glucuronidase expression was increased by TGF-beta and decreased by IFN-gamma, These responses were not modified by cytokines with the opposing function. Thus, the functional response of BMDMs to complex mixtures of cytokines was determined by the first cytokine to which they were exposed. Once activated, BMDMs become unresponsive to alternative activating signals, a finding which has obvious implications for M phi function in vivo.

AB - The functional properties of infiltrating macrophages (M phi) must be tightly regulated to facilitate appropriate responses to complex conditions in an inflammatory focus. This study was designed to ascertain whether uncommitted M phi that have been exposed to combinations of cytokines with opposing functions develop properties dictated by one cytokine or by cytokine mixtures. Uncommitted rat bone marrow-derived M phi (BMDMs) were incubated with IFN-gamma, TNF-alpha, TGF-beta, IL-4, IL-6, and IL-10 alone or sequentially in combinations. After 48 h, function was assessed by nitric oxide (NO) generation, uptake of apoptotic neutrophils, and beta-glucuronidase expression. IFN-gamma followed 4 h later by TNF-induced NO generation. The pretreatment of BMDMs before IFN-gamma priming with TNF, TGF-beta, and IL-4 suppressed NO generation by 87%, 92%, and 85%, respectively; IL-10 had no effect. The same cytokines administered at 4 h after IFN priming had no effect on NO generation. The uptake of apoptotic polymorphonuclear leukocytes was augmented by TNF (40% vs 29% controls; p < 0.05) and decreased by IFN-gamma, IL-10, and IL-4. The TNF response was unaffected by subsequent treatment with IFN-gamma, IL-4, or IL-10. Similarly, the decreased polymorphonuclear leukocyte uptake induced by IFN-gamma, IL-4, or IL-10 was unaffected by the subsequent addition of TNF. beta-glucuronidase expression was increased by TGF-beta and decreased by IFN-gamma, These responses were not modified by cytokines with the opposing function. Thus, the functional response of BMDMs to complex mixtures of cytokines was determined by the first cytokine to which they were exposed. Once activated, BMDMs become unresponsive to alternative activating signals, a finding which has obvious implications for M phi function in vivo.

KW - GROWTH-FACTOR-BETA

KW - NITRIC-OXIDE SYNTHASE

KW - NECROSIS-FACTOR-ALPHA

KW - ACTIVATED MACROPHAGE

KW - VITRONECTIN RECEPTOR

KW - MOUSE MACROPHAGES

KW - INTERFERON-GAMMA

KW - TNF-ALPHA

KW - IFN-GAMMA

KW - CELL

M3 - Article

VL - 161

SP - 1983

EP - 1988

JO - The Journal of Immunology

JF - The Journal of Immunology

SN - 0022-1767

IS - 4

ER -