Reverse signaling via CD30 ligand.
CD30 ligand (CD30L), a member of the TNF family, is a type II membrane protein with a C-terminal extracellular domain that is homologous with the extracellular domains of other TNF family members. Also, like most TNF family members, the N-terminal cytoplasmic domain of CD30L is conserved across species, but not between family members, suggesting a possible biological function. Motivated by this observation, we investigated the potential for CD30L, when activated by cross-linking, to directly transduce a signal to the ligand-bearing cell. Cross-linking of CD30L by a mAb or by CD30-Fc fusion protein induced the production of IL-8 by freshly isolated neutrophils. Further, both cross-linking mechanisms produced a rapid oxidative burst. Indirect effects through CD30 were ruled out, since CD30L, but not CD30, is expressed on neutrophils. Expression of CD30L can be induced in peripheral blood T cells by cross-linking the CD3 component of the TCR. Peripheral blood T cells exposed to suboptimal concentrations of anti-CD3 increased metabolic activity, proliferated, and produced IL-6 in response to cross-linking of CD30L. These results indicate that cross-linked CD30L can transduce a signal to the ligand-bearing cell. This "reverse signaling" via CD30L taken together with previously published data concerning other ligands in the TNF family strongly suggest that, as a rule, TNF family members and their cognate receptors signal bidirectionally, blurring the distinction between ligand and receptor.
Wiley
S R
SR
Immunex Corporation, Seattle, WA 98101, USA.
Goodwin
R G
RG
Smith
C A
CA
D000911:Antibodies, Monoclonal; D053285:CD30 Ligand; D003432:Cross-Linking Reagents / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D017730:Ki-1 Antigen / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D016897:Respiratory Burst; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D053285:CD30 Ligand; D003432:Cross-Linking Reagents; D015850:Interleukin-6; D016209:Interleukin-8; D017730:Ki-1 Antigen; D008024:Ligands; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; C505774:TNFSF8 protein, human