Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages.

Abstract

Vascular endothelial growth factor (VEGF) and VEGF receptor-1 (VEGFR-1/Flt-1) were shown to be involved in pathological angiogenesis, particularly rheumatoid arthritis (RA). However, the molecular basis of their actions is not fully understood. Here we report that in a murine model of RA, deletion of the tyrosine kinase (TK) domain of VEGFR-1 decreased the incidence and clinical symptoms of RA. Pathological symptoms, such as synovial hyperplasia, inflammatory infiltrates, pannus formation, and cartilage/bone destruction, became milder in Vegfr-1 tk(-/-) mice compared with wild-type (Wt) mice in the human T-cell leukemia virus-1 (HTLV-1) pX-induced chronic models. VEGFR-1 TK-deficient bone marrow cells showed a suppression of multilineage colony formation. Furthermore, macrophages induced to differentiate in vitro showed a decrease in immunologic reactions such as phagocytosis and the secretion of interleukin-6 (IL-6) and VEGF-A. Treatment of this RA model with a small molecule inhibitor for VEGFR TK, KRN951, also attenuated the arthritis. These results indicate that the VEGFR-1 TK signaling modulates the proliferation of bone marrow hematopoietic cells and immunity of monocytes/macrophages and promotes chronic inflammation, which may be a new target in the treatment of RA.

• Authors: Masato Murakami, Shinobu Iwai, Sachie Hiratsuka, Mai Yamauchi, Kazuhide Nakamura, Yoichiro Iwakura, Masabumi Shibuya
• Journal: Blood (Blood) Vol. 108 Issue 6 Pg. 1849-56 (Sep 15 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16709927 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Arthritis, Rheumatoid (etiology, immunology, pathology, physiopathology)
• Cytokines (biosynthesis)
• Female
• Hematopoiesis
• Macrophage Activation
• Male
• Mice
• Mice, Congenic
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (immunology)
• Phagocytosis
• Protein Structure, Tertiary
• Signal Transduction
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors, chemistry, deficiency, metabolism)