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Macrophage CD74 contributes to MIF-induced pulmonary inflammation

Takahashi, Koichiro; Koga, Kiyokazu; Linge, Helena LU ; Zhang, Yinzhong; Lin, Xinchun; Metz, Christine N; Al-Abed, Yousef; Ojamaa, Kaie and Miller, Edmund J (2009) In Respiratory Research 10.
Abstract

BACKGROUND: MIF is a critical mediator of the host defense, and is involved in both acute and chronic responses in the lung. Neutralization of MIF reduces neutrophil accumulation into the lung in animal models. We hypothesized that MIF, in the alveolar space, promotes neutrophil accumulation via activation of the CD74 receptor on macrophages.

METHODS: To determine whether macrophage CD74 surface expression contributes MIF-induced neutrophil accumulation, we instilled recombinant MIF (r-MIF) into the trachea of mice in the presence or absence of anti-CD74 antibody or the MIF specific inhibitor, ISO-1. Using macrophage culture, we examined the downstream pathways of MIF-induced activation that lead to neutrophil... (More)

BACKGROUND: MIF is a critical mediator of the host defense, and is involved in both acute and chronic responses in the lung. Neutralization of MIF reduces neutrophil accumulation into the lung in animal models. We hypothesized that MIF, in the alveolar space, promotes neutrophil accumulation via activation of the CD74 receptor on macrophages.

METHODS: To determine whether macrophage CD74 surface expression contributes MIF-induced neutrophil accumulation, we instilled recombinant MIF (r-MIF) into the trachea of mice in the presence or absence of anti-CD74 antibody or the MIF specific inhibitor, ISO-1. Using macrophage culture, we examined the downstream pathways of MIF-induced activation that lead to neutrophil accumulation.

RESULTS: Intratracheal instillation of r-MIF increased the number of neutrophils as well as the concentration of macrophage inflammatory protein 2 (MIP-2) and keratinocyte-derived chemokine (KC) in BAL fluids. CD74 was found to be expressed on the surface of alveolar macrophages, and MIF-induced MIP-2 accumulation was dependent on p44/p42 MAPK in macrophages. Anti-CD74 antibody inhibited MIF-induced p44/p42 MAPK phosphorylation and MIP-2 release by macrophages. Furthermore, we show that anti-CD74 antibody inhibits MIF-induced alveolar accumulation of MIP-2 (control IgG vs. CD74 Ab; 477.1 +/- 136.7 vs. 242.2 +/- 102.2 pg/ml, p < 0.05), KC (1796.2 +/- 436.1 vs. 1138.2 +/- 310.2 pg/ml, p < 0.05) and neutrophils (total number of neutrophils, 3.33 +/- 0.93 x 104 vs. 1.90 +/- 0.61 x 104, p < 0.05) in our mouse model.

CONCLUSION: MIF-induced neutrophil accumulation in the alveolar space results from interaction with CD74 expressed on the surface of alveolar macrophage cells. This interaction induces p44/p42 MAPK activation and chemokine release. The data suggest that MIF and its receptor, CD74, may be useful targets to reduce neutrophilic lung inflammation, and acute lung injury.

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published
keywords
Animals, Antigens, Differentiation, B-Lymphocyte, Disease Models, Animal, Histocompatibility Antigens Class II, Humans, Intramolecular Oxidoreductases, Macrophage Migration-Inhibitory Factors, Macrophages, Male, Mice, Mice, Inbred C57BL, Pneumonia, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
in
Respiratory Research
volume
10
publisher
BioMed Central
external identifiers
  • scopus:66649099110
ISSN
1465-9921
DOI
10.1186/1465-9921-10-33
language
English
LU publication?
no
id
0c828605-4cf2-4366-8765-a81a5f08299b
date added to LUP
2016-10-20 11:50:38
date last changed
2017-11-19 04:34:03
@article{0c828605-4cf2-4366-8765-a81a5f08299b,
  abstract     = {<p>BACKGROUND: MIF is a critical mediator of the host defense, and is involved in both acute and chronic responses in the lung. Neutralization of MIF reduces neutrophil accumulation into the lung in animal models. We hypothesized that MIF, in the alveolar space, promotes neutrophil accumulation via activation of the CD74 receptor on macrophages.</p><p>METHODS: To determine whether macrophage CD74 surface expression contributes MIF-induced neutrophil accumulation, we instilled recombinant MIF (r-MIF) into the trachea of mice in the presence or absence of anti-CD74 antibody or the MIF specific inhibitor, ISO-1. Using macrophage culture, we examined the downstream pathways of MIF-induced activation that lead to neutrophil accumulation.</p><p>RESULTS: Intratracheal instillation of r-MIF increased the number of neutrophils as well as the concentration of macrophage inflammatory protein 2 (MIP-2) and keratinocyte-derived chemokine (KC) in BAL fluids. CD74 was found to be expressed on the surface of alveolar macrophages, and MIF-induced MIP-2 accumulation was dependent on p44/p42 MAPK in macrophages. Anti-CD74 antibody inhibited MIF-induced p44/p42 MAPK phosphorylation and MIP-2 release by macrophages. Furthermore, we show that anti-CD74 antibody inhibits MIF-induced alveolar accumulation of MIP-2 (control IgG vs. CD74 Ab; 477.1 +/- 136.7 vs. 242.2 +/- 102.2 pg/ml, p &lt; 0.05), KC (1796.2 +/- 436.1 vs. 1138.2 +/- 310.2 pg/ml, p &lt; 0.05) and neutrophils (total number of neutrophils, 3.33 +/- 0.93 x 104 vs. 1.90 +/- 0.61 x 104, p &lt; 0.05) in our mouse model.</p><p>CONCLUSION: MIF-induced neutrophil accumulation in the alveolar space results from interaction with CD74 expressed on the surface of alveolar macrophage cells. This interaction induces p44/p42 MAPK activation and chemokine release. The data suggest that MIF and its receptor, CD74, may be useful targets to reduce neutrophilic lung inflammation, and acute lung injury.</p>},
  articleno    = {33},
  author       = {Takahashi, Koichiro and Koga, Kiyokazu and Linge, Helena and Zhang, Yinzhong and Lin, Xinchun and Metz, Christine N and Al-Abed, Yousef and Ojamaa, Kaie and Miller, Edmund J},
  issn         = {1465-9921},
  keyword      = {Animals,Antigens, Differentiation, B-Lymphocyte,Disease Models, Animal,Histocompatibility Antigens Class II,Humans,Intramolecular Oxidoreductases,Macrophage Migration-Inhibitory Factors,Macrophages,Male,Mice,Mice, Inbred C57BL,Pneumonia,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {05},
  publisher    = {BioMed Central},
  series       = {Respiratory Research},
  title        = {Macrophage CD74 contributes to MIF-induced pulmonary inflammation},
  url          = {http://dx.doi.org/10.1186/1465-9921-10-33},
  volume       = {10},
  year         = {2009},
}