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Involvement of the Cyclic AMP Pathway in Dendritic Cell Regulation of Th2 Immune Responses
Author(s) -
Chinn Amy M,
Lee Jihyung,
Herdman Scott,
Raz Eyal,
Insel Paul A
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.969.19
Subject(s) - gnas complex locus , cd11c , g protein coupled receptor , dendritic cell , gs alpha subunit , microbiology and biotechnology , biology , immune system , signal transduction , receptor , g protein , chemistry , phenotype , gene , immunology , biochemistry
Dendritic cells, the main antigen‐presenting cells, are involved in the induction of type II helper T cell (Th2) immune responses, but the mechanism by which this occurs is not fully elucidated. Mice that have a CD11c‐specific deletion of the Gnas gene (CD11c Δ Gnas ), which encodes the Gαs protein of the heterotrimeric (αβγ) Gs signaling protein complex, display an allergic asthma phenotype; the corresponding decrease in cyclic AMP (cAMP) in dendritic cells biases them to provoke a Th2 response ex vivo and in vivo (Lee et al PNAS 112: 1529–34 [2015]). The molecular events involved in the Th2 bias that results from the increased Gαi : Gαs signaling ratio in this setting remain to be defined. Here, we compare the expression of G protein‐coupled receptors (GPCRs), including those that regulate cAMP formation, and the expression of other components that regulate cAMP levels of wild‐type (WT) and CD11c Δ Gnas mouse bone marrow‐derived dendritic cells (BMDCs). Quantitative PCR (qPCR)‐based Taqman GPCR arrays revealed that WT BMDCs express 120 non‐chemosensory GPCRs while CD11c Δ Gnas BMDCs express 145 GPCRs. Notably, GPCRs that couple to Gαi (rather than other Gα proteins) have the greatest increase in gene expression in the CD11c Δ Gnas BMDCs compared to BMDCs from WT mice. Moreover, CD11c Δ Gnas BMDCs have reduced expression (as assayed by qPCR; p<0.05) of cyclic nucleotide phosphodiesterase (PDE) isoforms that degrade cAMP and are known to be induced by increases in cellular cAMP levels (PDE's1B, 3B, 4A, 4B, 4D, and 7B). PDE4B is also the predominant PDE isoform in mouse BMDCs. In addition, we found a significant (p<0.05) change in the mRNA expression of certain adenylyl cyclase isoforms: an increase in ADCY3 and decrease in ADCY4. Together, these data indicate that the expression of GPCRs (in particular Gαi‐coupled GPCRs) and other components that regulate cAMP levels are altered in dendritic cells that promote Th2 bias. Such GPCRs and post‐G protein components may contribute to the greater Th2 responses and allergic asthma observed in CD11c Δ Gnas mice. Support or Funding Information Supported by NIH grants R56AI110505 and T32GM007752.