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Targeted tumor necrosis factor receptor I preligand assembly domain improves skin lesions in MRL/lpr mice
Guo-Min Deng1, Lena Liu, George C Tsokos
1Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 937, Boston, MA 02115, USA. gdeng@bidmc.harvard.edu
Objective:
Skin disease is the second most common manifestation in patients with systemic lupus erythematosus (SLE). Tumor necrosis factor receptor (TNFR) preligand assembly domain (PLAD) has been found to block the effect of TNFalpha, and TNFRI PLAD (p60 PLAD) inhibits inflammatory arthritis. This study was undertaken to investigate whether TNFR PLAD limits inflammatory skin injury in a mouse model of SLE.
Methods:
Female MRL/lpr mice received p60 PLAD (100 microg/mouse intraperitoneally), p80 PLAD (100 microg/mouse intraperitoneally), or phosphate buffered saline (100 microl/mouse intraperitoneally) 3 times a week for 26 weeks, starting at age 6 weeks.
Results:
Immunohistochemistry studies demonstrated that TNFRI but not TNFRII was dominantly expressed in skin lesions in MRL/lpr mice. We found that TNFRI PLAD (p60 PLAD) but not TNFRII PLAD (p80 PLAD) protein significantly inhibited skin injury in the MRL/lpr mouse model of lupus. NF-kappaB, monocyte chemotactic protein 1, and inducible nitric oxide synthase expression in skin lesions were significantly inhibited by p60 PLAD. Lupus serum-induced monocyte differentiation into dendritic cells was reduced by p60 PLAD, but p60 PLAD did not reduce IgG deposition in the skin or improve the progression of kidney damage in MRL/lpr mice.
Conclusion:
Our results indicate that TNFRI is involved in the expression of skin injury in MRL/lpr mice with lupus and that p60 PLAD or similar biologics may be of clinical value if applied locally.
