| First Author | Ramachandran IR | Year | 2011 |
| Journal | J Immunol | Volume | 186 |
| Issue | 7 | Pages | 3934-45 |
| PubMed ID | 21357539 | Mgi Jnum | J:170692 |
| Mgi Id | MGI:4947154 | Doi | 10.4049/jimmunol.1001675 |
| Citation | Ramachandran IR, et al. (2011) The phosphatase SRC homology region 2 domain-containing phosphatase-1 is an intrinsic central regulator of dendritic cell function. J Immunol 186(7):3934-45 |
| abstractText | Dendritic cells (DCs) initiate proinflammatory or regulatory T cell responses, depending on their activation state. Despite extensive knowledge of DC-activating signals, the understanding of DC inhibitory signals is relatively limited. We show that Src homology region 2 domain-containing phosphatase-1 (SHP-1) is an important inhibitor of DC signaling, targeting multiple activation pathways. Downstream of TLR4, SHP-1 showed increased interaction with several proteins including IL-1R-associated kinase-4, and modulated LPS signaling by inhibiting NF-kappaB, AP-1, ERK, and JNK activity, while enhancing p38 activity. In addition, SHP-1 inhibited prosurvival signaling through AKT activation. Furthermore, SHP-1 inhibited CCR7 protein expression. Inhibiting SHP-1 in DCs enhanced proinflammatory cytokines, IL-6, IL-12, and IL-1beta production, promoted survival, and increased DC migration to draining lymph nodes. Administration of SHP-1-inhibited DCs in vivo induced expansion of Ag-specific cytotoxic T cells and inhibited Foxp3(+) regulatory T cell induction, resulting in an enhanced immune response against pre-established mouse melanoma and prostate tumors. Taken together, these data demonstrate that SHP-1 is an intrinsic global regulator of DC function, controlling many facets of T cell-mediated immune responses. |
