Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses

M. J. Ashbrook, K. L. Mcdonough, J. J. Pituch, P. L. Christopherson, T. T. Cornell, D. T. Selewski, T. P. Shanley, N. B. Blatt*

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Citrate, a central component of cellular metabolism, is a widely used anti-coagulant due to its ability to chelate calcium. Adenosine triphosphate (ATP)-citrate lyase, which metabolizes citrate, has been shown to be essential for inflammation, but the ability of exogenous citrate to impact inflammatory signalling cascades remains largely unknown. We hypothesized that citrate would modulate inflammatory responses as both a cellular metabolite and calcium chelator, and tested this hypothesis by determining how clinically relevant levels of citrate modulate monocyte proinflammatory responses to lipopolysaccharide (LPS) in a human acute monocytic leukaemia cell line (THP-1). In normal medium (0·4 mM calcium), citrate inhibited LPS-induced tumour necrosis factor (TNF)-α and interleukin (IL)-8 transcripts, whereas in medium supplemented with calcium (1·4 mM), TNF-α and IL-8 levels increased and appeared independent of calcium chelation. Using an IL-8-luciferase plasmid construct, the same increased response was observed in the activation of the IL-8 promoter region, suggesting transcriptional regulation. Tricarballylic acid, an inhibitor of ATP-citrate lyase, blocked the ability of citrate to augment TNF-α, linking citrate's augmentation effect with its metabolism by ATP-citrate lyase. In the presence of citrate, increased histone acetylation was observed in the TNF-α and IL-8 promoter regions of THP-1 cells. We observed that citrate can both augment and inhibit proinflammatory cytokine production via modulation of inflammatory gene transactivation. These findings suggest that citrate anti-coagulation may alter immune function through complex interactions with the inflammatory response.

Original languageEnglish (US)
Pages (from-to)520-530
Number of pages11
JournalClinical and Experimental Immunology
Volume180
Issue number3
DOIs
StatePublished - Jun 1 2015

Fingerprint

Citric Acid
Lipopolysaccharides
Monocytes
citrate (pro-3S)-lyase
Interleukin-8
Tumor Necrosis Factor-alpha
Adenosine Triphosphate
Calcium
Genetic Promoter Regions
Calcium Citrate
Leukemia, Monocytic, Acute
Coagulants
Acetylation
Luciferases
Histones
Transcriptional Activation
Plasmids
Cytokines
Inflammation
Cell Line

Keywords

  • Citrate
  • Epigenetics
  • Inflammation
  • Monocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Ashbrook, M. J., Mcdonough, K. L., Pituch, J. J., Christopherson, P. L., Cornell, T. T., Selewski, D. T., ... Blatt, N. B. (2015). Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses. Clinical and Experimental Immunology, 180(3), 520-530. https://doi.org/10.1111/cei.12591
Ashbrook, M. J. ; Mcdonough, K. L. ; Pituch, J. J. ; Christopherson, P. L. ; Cornell, T. T. ; Selewski, D. T. ; Shanley, T. P. ; Blatt, N. B. / Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses. In: Clinical and Experimental Immunology. 2015 ; Vol. 180, No. 3. pp. 520-530.
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Ashbrook, MJ, Mcdonough, KL, Pituch, JJ, Christopherson, PL, Cornell, TT, Selewski, DT, Shanley, TP & Blatt, NB 2015, 'Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses', Clinical and Experimental Immunology, vol. 180, no. 3, pp. 520-530. https://doi.org/10.1111/cei.12591

Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses. / Ashbrook, M. J.; Mcdonough, K. L.; Pituch, J. J.; Christopherson, P. L.; Cornell, T. T.; Selewski, D. T.; Shanley, T. P.; Blatt, N. B.

In: Clinical and Experimental Immunology, Vol. 180, No. 3, 01.06.2015, p. 520-530.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses

AU - Ashbrook, M. J.

AU - Mcdonough, K. L.

AU - Pituch, J. J.

AU - Christopherson, P. L.

AU - Cornell, T. T.

AU - Selewski, D. T.

AU - Shanley, T. P.

AU - Blatt, N. B.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Citrate, a central component of cellular metabolism, is a widely used anti-coagulant due to its ability to chelate calcium. Adenosine triphosphate (ATP)-citrate lyase, which metabolizes citrate, has been shown to be essential for inflammation, but the ability of exogenous citrate to impact inflammatory signalling cascades remains largely unknown. We hypothesized that citrate would modulate inflammatory responses as both a cellular metabolite and calcium chelator, and tested this hypothesis by determining how clinically relevant levels of citrate modulate monocyte proinflammatory responses to lipopolysaccharide (LPS) in a human acute monocytic leukaemia cell line (THP-1). In normal medium (0·4 mM calcium), citrate inhibited LPS-induced tumour necrosis factor (TNF)-α and interleukin (IL)-8 transcripts, whereas in medium supplemented with calcium (1·4 mM), TNF-α and IL-8 levels increased and appeared independent of calcium chelation. Using an IL-8-luciferase plasmid construct, the same increased response was observed in the activation of the IL-8 promoter region, suggesting transcriptional regulation. Tricarballylic acid, an inhibitor of ATP-citrate lyase, blocked the ability of citrate to augment TNF-α, linking citrate's augmentation effect with its metabolism by ATP-citrate lyase. In the presence of citrate, increased histone acetylation was observed in the TNF-α and IL-8 promoter regions of THP-1 cells. We observed that citrate can both augment and inhibit proinflammatory cytokine production via modulation of inflammatory gene transactivation. These findings suggest that citrate anti-coagulation may alter immune function through complex interactions with the inflammatory response.

AB - Citrate, a central component of cellular metabolism, is a widely used anti-coagulant due to its ability to chelate calcium. Adenosine triphosphate (ATP)-citrate lyase, which metabolizes citrate, has been shown to be essential for inflammation, but the ability of exogenous citrate to impact inflammatory signalling cascades remains largely unknown. We hypothesized that citrate would modulate inflammatory responses as both a cellular metabolite and calcium chelator, and tested this hypothesis by determining how clinically relevant levels of citrate modulate monocyte proinflammatory responses to lipopolysaccharide (LPS) in a human acute monocytic leukaemia cell line (THP-1). In normal medium (0·4 mM calcium), citrate inhibited LPS-induced tumour necrosis factor (TNF)-α and interleukin (IL)-8 transcripts, whereas in medium supplemented with calcium (1·4 mM), TNF-α and IL-8 levels increased and appeared independent of calcium chelation. Using an IL-8-luciferase plasmid construct, the same increased response was observed in the activation of the IL-8 promoter region, suggesting transcriptional regulation. Tricarballylic acid, an inhibitor of ATP-citrate lyase, blocked the ability of citrate to augment TNF-α, linking citrate's augmentation effect with its metabolism by ATP-citrate lyase. In the presence of citrate, increased histone acetylation was observed in the TNF-α and IL-8 promoter regions of THP-1 cells. We observed that citrate can both augment and inhibit proinflammatory cytokine production via modulation of inflammatory gene transactivation. These findings suggest that citrate anti-coagulation may alter immune function through complex interactions with the inflammatory response.

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KW - Epigenetics

KW - Inflammation

KW - Monocytes

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Ashbrook MJ, Mcdonough KL, Pituch JJ, Christopherson PL, Cornell TT, Selewski DT et al. Citrate modulates lipopolysaccharide-induced monocyte inflammatory responses. Clinical and Experimental Immunology. 2015 Jun 1;180(3):520-530. https://doi.org/10.1111/cei.12591