Cooperative regulation of NOTCH1 protein-phosphatidylinositol 3-kinase (PI3K) signaling by NOD1, NOD2, and TLR2 receptors renders enhanced refractoriness to transforming growth factor-beta (TGF-beta)- or cytotoxic T-lymphocyte antigen 4 (CTLA-4)-mediated impairment of human dendritic cell maturation.

Abstract

Dendritic cells (DCs) as sentinels of the immune system are important for eliciting both primary and secondary immune responses to a plethora of microbial pathogens. Cooperative stimulation of a complex set of pattern-recognition receptors, including TLR2 and nucleotide-binding oligomerization domain (NOD)-like receptors on DCs, acts as a rate-limiting factor in determining the initiation and mounting of the robust immune response. It underscores the need for "decoding" these multiple receptor interactions. In this study, we demonstrate that TLR2 and NOD receptors cooperatively regulate functional maturation of human DCs. Intriguingly, synergistic stimulation of TLR2 and NOD receptors renders enhanced refractoriness to TGF-β- or CTLA-4-mediated impairment of human DC maturation. Signaling perturbation data suggest that NOTCH1-PI3K signaling dynamics assume critical importance in TLR2- and NOD receptor-mediated surmounting of CTLA-4- and TGF-β-suppressed maturation of human DCs. Interestingly, the NOTCH1-PI3K signaling axis holds the capacity to regulate DC functions by virtue of PKCδ-MAPK-dependent activation of NF-κB. This study provides mechanistic and functional insights into TLR2- and NOD receptor-mediated regulation of DC functions and unravels NOTCH1-PI3K as a signaling cohort for TLR2 and NOD receptors. These findings serve in building a conceptual foundation for the design of improved strategies for adjuvants and immunotherapies against infectious diseases.

• Authors: Devram Sampat Ghorpade, Srini V Kaveri, Jagadeesh Bayry, Kithiganahalli Narayanaswamy Balaji
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 36 Pg. 31347-60 (Sep 09 2011) ISSN: 1083-351X [Electronic] United States
• PMID: 21768114 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• CTLA-4 Antigen
• CTLA4 protein, human
• NF-kappa B
• NOD1 protein, human
• NOD2 protein, human
• Nod1 Signaling Adaptor Protein
• Nod2 Signaling Adaptor Protein
• Receptor, Notch1
• TLR2 protein, human
• Toll-Like Receptor 2
• Transforming Growth Factor beta
• Phosphatidylinositol 3-Kinase

Topics

• CTLA-4 Antigen (immunology)
• Cell Differentiation (immunology)
• Dendritic Cells (cytology, immunology)
• Humans
• NF-kappa B (metabolism)
• Nod1 Signaling Adaptor Protein (immunology, metabolism)
• Nod2 Signaling Adaptor Protein (immunology, metabolism)
• Phosphatidylinositol 3-Kinase (immunology, metabolism)
• Receptor, Notch1 (immunology, metabolism)
• Signal Transduction (immunology)
• Toll-Like Receptor 2 (immunology, metabolism)
• Transforming Growth Factor beta (immunology)