Low herpesvirus entry mediator (HVEM) expression on dermal fibroblasts contributes to a Th2-dominant microenvironment in advanced cutaneous T-cell lymphoma.
LIGHT (lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes) is a ligand for HVEM. LIGHT-HVEM interactions are important in T helper type 1 (Th1) immune responses. In some cases with early stages of cutaneous T cell lymphoma (CTCL), IL-2, IFN-γ, and Th1 chemokines are expressed in lesional skin, while IL-4, IL-5, and Th2 chemokines are dominant in advanced CTCL. In this study, we investigated roles of LIGHT and HVEM in the microenvironment of CTCL. LIGHT enhanced production of Th1 chemokines, such as CXC chemokine ligand (CXCL) 9, CXCL10, and CXCL11, from IFN-γ-treated dermal fibroblasts via phosphorylation of inhibitor κBα. Messenger RNA levels of these chemokines were increased in lesional skin of early CTCL. Interestingly, while LIGHT expression in CTCL skin correlated with disease progression, HVEM expression was significantly decreased in advanced CTCL skin. HVEM was detected in dermal fibroblasts in early CTCL skin, but not in advanced CTCL skin in situ. These results suggest that low HVEM expression on dermal fibroblasts in advanced CTCL skin attenuates expression of Th1 chemokines, which may contribute to a shift to a Th2-dominant microenvironment as disease progresses.
Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Tomomitsu
T
Miyagaki
Makoto
M
Sugaya
Hiraku
H
Suga
Sohshi
S
Morimura
Hanako
H
Ohmatsu
Hideki
H
Fujita
Yoshihide
Y
Asano
Yayoi
Y
Tada
Takafumi
T
Kadono
Shinichi
S
Sato
D000328:Adult; D000368:Aged; D001706:Biopsy; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D012333:RNA, Messenger / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018418:Th2 Cells / Q000473:pathology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism
D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma