Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2

C. M. Hogaboam, C. L. Bone-Larson, M. L. Steinhauser, Akihiro Matsukawa, J. Gosling, L. Boring, I. F. Charo, K. J. Simpson, N. W. Lukacs, S. L. Kunkel

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Abstract

Monocyte chemoattractant protein-1 is one of the major C-C chemokines that has been implicated in liver injury. The C-C chemokine receptor, CCR2, has been identified as the primary receptor that mediates monocyte chemoattractant protein-1 (MCP-1) responses in the mouse. Accordingly, the present study addressed the role of CCR2 in mice acutely challenged with acetaminophen (APAP). Mice genetically deficient in CCR2 (CCR2(-/-)) and their wild-type counterparts (CCR2(+/+)) were fasted for 10 hours before receiving an intraperitoneal injection of APAP (300 mg/kg). Liver and serum samples were removed from both groups of mice before and at 24 and 48 hours post APAP. Significantly elevated levels of MCP-1 were detected in liver samples from CCR2(+/+) and CCR2(-/-) mice at 24 hours post-APAP. Although CCR2(+/+) mice exhibited no liver injury at any time after receiving APAP, CCR2(-/-) mice exhibited marked evidence of necrotic and TUNEL-positive cells in the liver, particularly at 24 hours post-APAP. Enzyme-linked immunosorbent assay analysis of liver homogenates from both groups of mice at the 24 hours time point revealed that liver tissue from CCR2(-/-) mice contained significantly greater amounts of immunoreactive IFN-γ and TNF-α. The in vivo immunoneutralization of IFN-γ or TNF-α significantly attenuated APAP-induced liver injury in CCR2(-/-) mice and increased hepatic IL-13 levels. Taken together, these findings demonstrate that CCR2 expression in the liver provides a hepatoprotective effect through its regulation of cytokine generation during APAP challenge.

Original languageEnglish
Pages (from-to)1245-1252
Number of pages8
JournalAmerican Journal of Pathology
Volume156
Issue number4
Publication statusPublished - 2000
Externally publishedYes

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CC Chemokines
Chemokine Receptors
Acetaminophen
Liver
Wounds and Injuries
Chemokine CCL2
CCR2 Receptors
Interleukin-13
In Situ Nick-End Labeling
Intraperitoneal Injections
Enzyme-Linked Immunosorbent Assay
Cytokines

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Hogaboam, C. M., Bone-Larson, C. L., Steinhauser, M. L., Matsukawa, A., Gosling, J., Boring, L., ... Kunkel, S. L. (2000). Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2. American Journal of Pathology, 156(4), 1245-1252.

Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2. / Hogaboam, C. M.; Bone-Larson, C. L.; Steinhauser, M. L.; Matsukawa, Akihiro; Gosling, J.; Boring, L.; Charo, I. F.; Simpson, K. J.; Lukacs, N. W.; Kunkel, S. L.

In: American Journal of Pathology, Vol. 156, No. 4, 2000, p. 1245-1252.

Research output: Contribution to journalArticle

Hogaboam, CM, Bone-Larson, CL, Steinhauser, ML, Matsukawa, A, Gosling, J, Boring, L, Charo, IF, Simpson, KJ, Lukacs, NW & Kunkel, SL 2000, 'Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2', American Journal of Pathology, vol. 156, no. 4, pp. 1245-1252.
Hogaboam CM, Bone-Larson CL, Steinhauser ML, Matsukawa A, Gosling J, Boring L et al. Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2. American Journal of Pathology. 2000;156(4):1245-1252.
Hogaboam, C. M. ; Bone-Larson, C. L. ; Steinhauser, M. L. ; Matsukawa, Akihiro ; Gosling, J. ; Boring, L. ; Charo, I. F. ; Simpson, K. J. ; Lukacs, N. W. ; Kunkel, S. L. / Exaggerated hepatic injury due to acetaminophen challenge in mice lacking C-C chemokine receptor 2. In: American Journal of Pathology. 2000 ; Vol. 156, No. 4. pp. 1245-1252.
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AU - Matsukawa, Akihiro

AU - Gosling, J.

AU - Boring, L.

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AU - Simpson, K. J.

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AU - Kunkel, S. L.

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