Involvement of Gr-1dull+ Cells in the Production of TNF-α and IL-17 and Exacerbated Systemic Inflammatory Response Caused by Lipopolysaccharide
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Systemic inflammatory response syndrome (SIRS) is a life-threatening disease. Recent reports have demonstrated that the immunoregulatory cells that express Gr-1, a granulocyte surface antigen, play a critical role in various pathological conditions. In the present study, we have established a mouse model of SIRS and addressed the possible contribution of Gr-1+ cells in this model. C57BL/6 mice were injected intraperitoneally with anti-Gr-1 mAb or control IgG 1 day before administration of lipopolysaccharide (LPS). All of the mice that received anti-Gr-1 mAb and LPS died early as a result of hypothermia and severe emaciation, whereas mice treated with control IgG and LPS survived the observation period. In mice treated with anti-Gr-1 mAb and LPS, acute inflammatory changes with alveolar hemorrhage were observed in the lung and proximal convoluted tubule necrosis was observed in the kidney. Serum TNF-α and IL-17A levels were markedly increased in anti-Gr-1 mAb-pretreated mice compared with those in control IgG-treated mice at 1 and 3 h after LPS administration, respectively. Flow cytometric analysis revealed an increase in TNF-α and IL-17A expression in Gr-1dull+ cells in the peripheral blood mononuclear cells. Neutralization of TNF-α by a specific mAb almost completely reversed the clinical course and inhibited the increased production of IL-17A. In addition, IL-17A KO mice were less susceptible to the lethality in this model. Thus, we established a mouse model of severe SIRS and suggested that Gr-1dull+ cells may play a critical role in the development of this pathological condition.
KEY WORDSSystemic inflammatory response syndrome (SIRS) Gr-1 Lipopolysaccharide Mice
The authors thank Dr. Fujiro Sendo (Yamagata University, Yamagata, Japan) and Dr. Akio Nakane (Hirosaki University Graduate School of Medicine, Hirosaki, Japan) for their kind gifts of anti-Gr-1 mAb and anti-TNF-α mAb, respectively. This work was supported in part by a Grant from the Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Challenging Exploratory Research (23659841)) and a Grant from the Ministry of Health, Labor and Welfare of Japan (Research on Emerging and Re-emerging Infectious Diseases; 22-SHINKOU-IPPAN-014).
Conflict of interest
The authors declare that they have no financial conflicts of interest.
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