Abstract
Coccidioides posadasii spherules stimulate macrophages to make cytokines via TLR-2 and Dectin-1. We used formalin-killed spherules and 1,3-beta-glucan purified from spherules to stimulate elicited peritoneal macrophages and myeloid dendritic cells (mDCs) from susceptible (C57BL/6) and resistant (DBA/2) mouse strains. DBA/2 macrophages produced more TNF-alpha and IL-6 than macrophages from C57BL/6 mice, and the amount of TNF-alpha made was dependent on both TLR2 and Dectin-1. DCs from C57BL/6 mice made more IL-10 and less IL-23p19 and IL-12p70 than did DBA/2 DC. These responses were inhibited by a monoclonal antibody to Dectin-1. DBA/2 mice expressed full-length Dectin-1, whereas C57BL/6 mice spliced out exon 3, which encodes most of the stalk. RAW cells transduced to express the full-length Dectin-1 responded better to FKS than cells expressing truncated Dectin-1. We compared the isoform of Dectin-1 expressed by 34 C57BL/6 X DBA/2 recombinant inbred (BXD RI) lines with their susceptibility to Coccidioides immitis. In 25 of 34 RI lines susceptibility or resistance corresponded to short or full-length isoforms, respectively. These results suggest that alternative splicing of the Dectin-1 gene contributes to susceptibility of C57BL/6 mice to coccidioidomycosis, and affects the cytokine responses of macrophages and mDCs to spherules.
Original language | English |
---|---|
Pages (from-to) | 338-348 |
Number of pages | 11 |
Journal | Genes and Immunity |
Volume | 9 |
Issue number | 4 |
Early online date | 17 Apr 2008 |
DOIs | |
Publication status | Published - Jun 2008 |
Keywords
- alternative splicing
- animals
- cell line
- coccidioides
- coccidioidomycosis
- dendritic cells
- gene expression
- genetic predisposition to disease
- immunity, innate
- interleukin-10
- macrophages, peritoneal
- membrane proteins
- mice
- mice, inbred C57BL
- mice, inbred DBA
- nerve tissue proteins
- protein isoforms
- species specificity
- tumor necrosis factor-alpha