Human β-defensin 3 induces STAT1 phosphorylation, tyrosine phosphatase activity, and cytokine synthesis in T cells
Abstract
The AMP hBD-3 stimulates numerous immune effector functions in myeloid cells and keratinocytes, predominantly through the MAPK signaling cascade. In contrast, hBD-3 was reported to neutralize the activation of T cells by antagonizing MAPK signaling initiated by SDF-1α through CXCR4. With the use of complementary proteomic and immunochemical approaches, we investigated possible stimulatory effects of hBD-3 on T cells and demonstrate that hBD-3 induces STAT1 tyrosine phosphorylation within 5 min yet is unable to induce MAPK activation. Inclusion of a PTPase inhibitor increased hBD-3-induced phosphorylation dramatically, suggesting that hBD-3 also stimulates PTPase activity concurrently. The increase in PTPase activity was confirmed by demonstrating that hBD-3 suppresses IFN-γ-induced STAT1 tyrosine phosphorylation but not STAT1 serine and ERK1/2 threonine phosphorylation and stimulates the translocation of SHP-2 into the nucleus within 15 min. The signaling pathways initiated by hBD-3 may lead to the observed enhancement of distinct T cell effector functions during TCR activation, such as the increase in IL-2 and IL-10, but not IFN-γ secretion. Thus, hBD-3 initiates distinct lineage-specific signaling cascades in various cells involved in host defense and induces a concurrent tyrosine kinase and tyrosine phosphatase signaling cascade that may activate simultaneously the targeted T cells and inhibit their response to other immune mediators. Furthermore, these results suggest that this evolutionarily conserved peptide, which exhibits a broad spectrum of antimicrobial and immunomodulatory activities, serves to integrate innate and adaptive immunity.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 26, 2013
- Source ID
- 10.1189/jlb.0612300
Entities
People
- Alan D Levine
- Daniela M Schlatzer
- Jeffrey P Meisch
- Mark R. Chance
- Ryan M Vogel
- Xiaolin Li
Organizations
- Case Western Reserve University
- Crohn's & Colitis Foundation of America
- Medical Research Council