| First Author | Blaauboer SM | Year | 2014 |
| Journal | J Immunol | Volume | 192 |
| Issue | 1 | Pages | 492-502 |
| PubMed ID | 24307739 | Mgi Jnum | J:207163 |
| Mgi Id | MGI:5554616 | Doi | 10.4049/jimmunol.1301812 |
| Citation | Blaauboer SM, et al. (2014) MPYS/STING-mediated TNF-alpha, not type I IFN, is essential for the mucosal adjuvant activity of (3'-5')-cyclic-di-guanosine-monophosphate in vivo. J Immunol 192(1):492-502 |
| abstractText | The bacterial second messenger (3'-5')-cyclic-di-guanosine-monophosphate (CDG) is a promising mucosal adjuvant candidate that activates balanced Th1/Th2/Th17 responses. We showed previously that CDG activates stimulator of IFN genes (STING)-dependent IFN-I production in vitro. However, it is unknown whether STING or IFN-I is required for the CDG adjuvant activity in vivo. In this study, we show that STING(-/-) mice (Tmem173(<tm1Camb>)) do not produce Ag-specific Abs or Th1/Th2/Th17 cytokines during CDG/Ag immunization. Intranasal administration of CDG did not induce TNF-alpha, IL-1beta, IL-6, IL-12, or MCP-1 production in STING(-/-) mice. Surprisingly, we found that the cytokine and Ab responses were unaltered in CDG/Ag-immunized IFNAR(-/-) mice. Instead, we found that CDG activates STING-dependent, IFN-I-independent TNF-alpha production in vivo and in vitro. Furthermore, using a TNFR1(-/-) mouse, we demonstrate that TNF-alpha signaling is critical for CDG-induced Ag-specific Ab and Th1/Th2 cytokine production. This is distinct from STING-mediated DNA adjuvant activity, which requires IFN-I, but not TNF-alpha, production. Finally, we found that CDG activates STING-dependent, but IRF3 stimulation-independent, NF-kappaB signaling. Our results established an essential role for STING-mediated TNF-alpha production in the mucosal adjuvant activity of CDG in vivo and revealed a novel IFN-I stimulation-independent STING-NF-kappaB-TNF-alpha pathway. |
