TY - JOUR
T1 - TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus
AU - Doerner, Jessica L.
AU - Wen, Jing
AU - Xia, Yumin
AU - Paz, Karin Blecher
AU - Schairer, David
AU - Wu, Lan
AU - Chalmers, Samantha A.
AU - Izmirly, Peter
AU - Michaelson, Jennifer S.
AU - Burkly, Linda C.
AU - Friedman, Adam J.
AU - Putterman, Chaim
N1 - Publisher Copyright:
© 2015 The Society for Investigative Dermatology.
PY - 2015/8/21
Y1 - 2015/8/21
N2 - Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention.
AB - Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention.
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U2 - 10.1038/jid.2015.124
DO - 10.1038/jid.2015.124
M3 - Article
C2 - 25826425
AN - SCOPUS:84937630064
SN - 0022-202X
VL - 135
SP - 1986
EP - 1995
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 8
ER -