Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease.
CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7-1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H-RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD.
Gruss
H J
HJ
Department of Biochemistry, Immunex Research and Development Corp, Seattle, WA 98101.
Hirschstein
D
D
Wright
B
B
Ulrich
D
D
Caligiuri
M A
MA
Barcos
M
M
Strockbine
L
L
Armitage
R J
RJ
Dower
S K
SK
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism; D019013:CD40 Antigens; D023201:CD40 Ligand; D005260:Female; D015870:Gene Expression; D006689:Hodgkin Disease / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D017730:Ki-1 Antigen / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D016539:Reed-Sternberg Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D018122:B7-1 Antigen; D019013:CD40 Antigens; D017730:Ki-1 Antigen; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand