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.
Macrophage Migration Inhibitory Factor Plays an Important Role in Inflammatory Arthritis.
Amin2, Mohammad A., Ruth2, Jeffrey H., Rabquer2, Bradley J., Campbell2, Phillip L., Lee2, Solhee, David1, John R., Koch3, Alisa E.
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine which plays an important role in chronic inflammatory diseases such as rheumatoid arthritis (RA). We have previously shown that MIF mediates angiogenesis via phosphatidylinositol 3 kinase (PI3K) and mitogen activated protein kinase, and upregulates the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in monocytes via Src, PI3K, and NFkB. In this study, we examined the contribution of MIF to experimental inflammatory arthritis using K/BxN serum induced arthritis by employing MIF null and wild type (wt) mice.
We induced serum transfer K/BxN arthritis in MIF null and wt mice to examine the role of MIF in mouse inflammatory arthritis. We injected 150 ml of pooled K/BxN serum on days 0 and 2. Mice were scored clinically and ankle circumference was measured with a caliper before the induction of arthritis and then every day by an observer blinded to the experimental groups. We used enzyme linked immunosorbent (ELISA) assays to determine cytokine levels in arthritic MIF null ankle homogenates compared to wt mouse ankle homogenates. We also performed immunohistochemistry (IHC) to determine the inflammatory response in MIF null and wt mouse ankle sections. To further elucidate the contribution of MIF in an animal model of arthritis, we subjected MIF null and wt mice to sublethal total body irradiation. We performed bone marrow transfer experiments. In these experiments, irradiated MIF null mice received wt bone marrow cells (106 cells in 100 ml of PBS) and vice versa. After 12 weeks of bone marrow transplant we induced K/BxN arthritis in these mice and collected ankles.
MIF null mice had significantly less arthritis, showing a significant decrease in ankle circumference and articular index compared to wt mice. Mouse ankles were harvested on day 9 (day of maximal arthritis). Some of ankles were snap frozen for homogenization and cytokine analysis, while others were frozen in OCT for histology. While there was no difference in interleukin-1b in mouse ankle joint homogenates, monocyte chemoattractant protein-1 (MCP-1/CCL2) was significantly decreased in MIF null mouse arthritic ankle homogenates compared to wt mouse arthritic ankles. This decrease was ~ 2 fold, suggesting an important role of MIF in the regulation of MCP-1/CCL2). IHC of MIF null ankle sections revealed reduced inflammation compared to wt mice. There was a marked decrease in MCP-1/CCL2 levels in irradiated wt mice injected with bone marrow harvested from MIF null mice compared to irradiated MIF null mice which received wt bone marrow, further confirming the significance of MIF in inflammatory arthritis.
These data suggest an important role for MIF in induction of MCP-1/CCL2 in mouse inflammatory arthritis. MIF may be a potential therapeutic target for the treatment of chronic inflammatory diseases like RA.
To cite this abstract, please use the following information:
Amin, Mohammad A., Ruth, Jeffrey H., Rabquer, Bradley J., Campbell, Phillip L., Lee, Solhee, David, John R., et al; Macrophage Migration Inhibitory Factor Plays an Important Role in Inflammatory Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1721