Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Lower Expression of Fli-1 Leads to Decreased Inflammatory Cell Infiltration in the Kidneys from NZM2410 Mice.
Williams4, Sarah, Reyes-Cortes2, Emmanuel, Karam3, Eva, Suzuki3, Eiji, Gilkeson1, Gary S., Zhang5, John
Med Univ of South Carolina, Charleston, SC
Medical University of South Carolina, Charleston, SC
Medical University of South Carolina
Ralph H. Johnson VA Medical Center, Charleston, SC
Ralph H. Johnson VA Medical Center and Medical University of South Carolina, Charleston, SC
Background and Purpose:
Fli-1 expression levels, a member of the Ets family of transcription factors, are a mitigating factor in the development of nephritis in murine models of systemic lupus erythematosus (SLE). Lupus nephritis is a major cause of death in both models and human patients, and is characterized by immune complex formation and inflammatory cell infiltration. Overexpression of the Fli-1 protein in transgenic mice resulted in the development of a lupus-like disease with nephritis. Expression of Fli-1 in SLE patients and animal models of lupus is higher compared to normal controls. In this study, we examined the effects of reduced Fli-1 expression on inflammatory cell infiltration in conjunction with nephritis development in NZM2410 mice, an animal model of SLE.
We generated Fli-1 heterozygous knockout NZM2410 mice (Fli1+/-; Fli-1 homozygous knockout is embryonic lethal) and wild-type (WT) littermate (Fli1+/+) mice for use as controls. The expression levels of monocyte chemotactic protein-1 (MCP-1) and Chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES) in the kidneys from 18-week-old mice were analyzed by real-time PCR. Pathological scores of the kidneys from 34-week-old mice were assessed and the number of macrophages, neutrophils, T cells and B cells in the kidneys were stained with specific antibodies and counted in 10 random high power fields (HPF). These numbers were averaged and directly compared between WT and Fli-1+/- NZM2410 mice. The MCP-1 in serum was measured by ELISA.
Since expression of CCL5 and MCP-1 were demonstrated to initiate inflammatory cell infiltration in the kidneys of lupus mice, we first examined the expression of MCP-1 and CCL5 in the kidneys from both Fli-1+/- and WT controls. Expression of MCP-1 and CCL5 in the kidneys from 18-week old Fli-1+/- NZM2410 mice was significantly decreased compared to that from WT littermates. Fli-1+/- NZM2410 mice also had significantly reduced renal pathology scores compared to those from WT littermates (WT mice: 6.846 ± 0.9635; Fli-1+/- mice: 3.882 ± 1.043, p< 0.05). The number of macrophages, neutrophil granulocytes, T cells and B cells in the kidneys from Fli-1+/- NZM2410 mice decreased by 44 75% compared to WT littermate controls. The serum MCP-1 levels in Fli-1+/- NZM2410 mice were significantly lower at the age of 34 weeks compared with WT littermates (WT mice: 118.9 ± 17.7 pg/ml; Fli-1+/- mice: 67.7 ± 7.1 pg/ml, p< 0.01).
Our data indicate that lower expression of Fli-1 results in decreased expression of CCL5 and MCP-1 in the kidneys with significantly reduced infiltration of inflammatory cells, which leads to lower overall kidney pathological scores in NZM2410 mice. Therefore, Fli-1 plays an important role in the development of nephritis in NZM2410 mice.
To cite this abstract, please use the following information:
Williams, Sarah, Reyes-Cortes, Emmanuel, Karam, Eva, Suzuki, Eiji, Gilkeson, Gary S., Zhang, John; Lower Expression of Fli-1 Leads to Decreased Inflammatory Cell Infiltration in the Kidneys from NZM2410 Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1526