Decoy Receptor 3 Suppresses TLR2-Mediated B Cell Activation by Targeting NF-κB

Abstract

Decoy receptor 3 (DcR3) is a soluble protein in the TNFR superfamily. Its known ligands include Fas ligand, homologous to lymphotoxin, showing inducible expression, and competing with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes, TNF-like molecule 1A, and heparan sulfate proteoglycans. DcR3 has been reported to modulate the functions of T cells, dendritic cells, and macrophages; however, its role in regulating B cell activation is largely unknown. In this study, we found that the DcR3.Fc fusion protein bound to human and mouse B cells and suppressed the activation of B cells. DcR3.Fc attenuated Staphylococcus aureus, IgM-, Pam3CSK4-, and LPS-mediated B cell proliferation but did not affect cytokine-induced B cell growth. In the presence of these mitogens, DcR3.Fc did not induce B cell apoptosis, suggesting that DcR3 may inhibit the signal(s) important for B cell activation. Because the combination of Fas.Fc, LT-βR.Fc (homologous to lymphotoxin, showing inducible expression, and competing with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes receptor), and DR3.Fc (TNF-like molecule 1A receptor) did not suppress B cell proliferation and because the biological effect of DcR3.Fc on B cells was not blocked by heparin, we hypothesize that a novel ligand(s) of DcR3 mediates its inhibitory activity on B cells. Moreover, we found that TLR2-stimulated NF-κB p65 activation and NF-κB–driven luciferase activity were attenuated by DcR3.Fc. The TLR2-induced cytokine production by B cells was consistently reduced by DcR3. These results imply that DcR3 may regulate B cell activation by suppressing the activation of NF-κB.

Shared genetic determinants between eczema and other immune-related diseases

“…On chromosome 5q22.1, the associated region includes TMEM232 (transmembrane protein 232) and SLC25A46 (solute carrier family 25, member 46), the functions of which are unknown. TNFRSF6B encodes decoy receptor 3 (DcR3), a secreted protein with various functions in adaptive immunity, including the response to Staphylococcus aureus infections that are characteristic of eczema [22]. On chromosome 20q13.33, the risk locus comprises eight genes with tumor necrosis factor receptor superfamily, member 6b, decoy (TNFRSF6B) being the best candidate.…”

Toll-like Receptor 1/2 Agonist Pam3CSK4 Suppresses Lipopolysaccharide-driven IgG1 Production while Enhancing IgG2a Production by B Cells

“…This indicates that different induction of NF-κB/Rel proteins has different effect on GLTγ1 transcription. NF-κB subunit p65 is activated by Pam3CSK4, which is important for Pam3CSK4-medicated B cell activation ( 51 52 ). Therefore, it is possible that LPS-induced NF-κB activation for GLTγ1 transcription was blocked by either binding of other Pam3CSK4-induced NF-κB complexes on GLTγ1 promoter region or competition between LPS- and Pam3CSK4-induced NF-κB subunits for functional NF-κB complex formation.…”

Decoy receptor 3: an endogenous immunomodulator in cancer growth and inflammatory reactions

“…b DcR3 modulates B cell activation via a yet-identified ligand on B cells. DcR3.Fc suppresses TLR2 ligand (Pam3CSK4) and Staphylococcus aureus cowan (SAC) strain-induced B cell activation via binding non-HSPG ligand(s) on B cells B cells: DcR3.Fc is able to suppress Staphylococcus aureus Cowan (SAC) strain-induced B cell proliferation as well as TLR2-induced TNF-α secretion [87], NFκB activation, and cytokine (IL-6, TNF-α, IL-12p40, IL-10) secretion via an unknown factor distinct from HSPGs, because DcR3.Fc-mediated effect is not blocked by heparin or heparan sulfate [88]. Unlike myeloid cells, addition of heparin does not inhibit DcR3.Fc binding to B cells (Fig.…”

“…DcR3.Fc is able to suppress Staphylococcus aureus Cowan (SAC) strain-induced B cell proliferation as well as TLR2-induced TNF-α secretion [87], NFκB activation, and cytokine (IL-6, TNF-α, IL-12p40, IL-10) secretion via an unknown factor distinct from HSPGs, because DcR3.Fc-mediated effect is not blocked by heparin or heparan sulfate [88]. Unlike myeloid cells, addition of heparin does not inhibit DcR3.Fc binding to B cells (Fig.…”