Article ; Online: Selective suppression of IL-10 transcription by calcineurin in dendritic cells through inactivation of CREB.
2021 Volume 34, Issue 4, Page(s) 197–206
Abstract: Myeloid cells play a pivotal role in immune responses against bacterial and fungal infection. Among innate immune receptors, C-type lectin receptors (CLRs) can induce a wide spectrum of cytokines through immunoreceptor tyrosine-based activation motifs ( ... ...
| Abstract | Myeloid cells play a pivotal role in immune responses against bacterial and fungal infection. Among innate immune receptors, C-type lectin receptors (CLRs) can induce a wide spectrum of cytokines through immunoreceptor tyrosine-based activation motifs (ITAMs)-mediated signaling pathways. Dendritic cells (DCs) produce IL-10 through CLR stimulation; however, the regulatory mechanism of IL-10 expression has not been elucidated. In the current study, we report that calcium (Ca2+) signaling-deficient DCs produced more IL-10 than wild-type DCs. Mechanistically, Ca2+-dependent phosphatase calcineurin directly inactivates cAMP response element-binding protein (CREB), a transcription factor of Il10 in DCs, through dephosphorylating CREB at serine 133. In calcineurin-deficient DCs, CREB was highly phosphorylated and increased its binding to the Il10 promoter. Elimination of mitogen-activated protein kinase (MAPK) signaling that phosphorylates CREB, deficiency of CREB, as well as deletion of a CREB-binding site in the Il10 promoter could diminish IL-10 production in DCs. Our findings identified a novel substrate of calcineurin as well as a mechanism through which Ca2+ signaling regulates IL-10 expression downstream of CLRs. As IL-10 is a crucial immunosuppressive cytokine, this mechanism may counteract the over-activated IL-10-producing signals induced by CARD9 and MAPK pathways, preventing the ineffectiveness of the immune system during bacterial and fungal infection. |
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| MeSH term(s) | Calcineurin/metabolism ; Calcium/metabolism ; Cyclic AMP Response Element-Binding Protein/metabolism ; Cytokines/metabolism ; Dendritic Cells ; Interleukin-10 ; Lectins, C-Type ; Phosphorylation |
| Chemical Substances | Cyclic AMP Response Element-Binding Protein ; Cytokines ; Lectins, C-Type ; Interleukin-10 (130068-27-8) ; Calcineurin (EC 3.1.3.16) ; Calcium (SY7Q814VUP) |
| Language | English |
| Publishing date | 2021-12-24 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1013745-2 |
| ISSN | 1460-2377 ; 0953-8178 |
| ISSN (online) | 1460-2377 |
| ISSN | 0953-8178 |
| DOI | 10.1093/intimm/dxab112 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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