Involvement of Gr-1dull+ Cells in the Production of TNF-α and IL-17 and Exacerbated Systemic Inflammatory Response Caused by Lipopolysaccharide

• DOI: 10.1007/s10753-013-9729-5
• Publication Date: 2013-09-11T01:21:36Z
• Authors: Daiki Tanno; Yukiko Akahori; Masahiko Toyama; Ko Sato; Daisuke Kudo; Yuzuru Abe; Tomomitsu Miyasaka; Hideki Yamamoto; Keiko Ishii; Emi Kanno; Ryoko Maruyama; Shigeki Kushimoto; Yoichiro Iwakura; Kazuyoshi Kawakami
• Keywords: Lipopolysaccharides; Male; Mice, Knockout; 0301 basic medicine; Tumor Necrosis Factor-alpha; Interleukin-17; Antibodies, Monoclonal; Hemorrhage; Systemic Inflammatory Response Syndrome; 3. Good health; Mice, Inbred C57BL; Pulmonary Alveoli; Mice; 03 medical and health sciences; Kidney Tubules; Immunoglobulin G; Leukocytes, Mononuclear; Animals; Female; Receptors, Chemokine

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-1 dull+ 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-1 dull+ cells may play a critical role in the development of this pathological condition.