Inflammation-dependent secretion and splicing of IL-32{gamma} in rheumatoid arthritis.

ABSTRACT: Different splice variants of the proinflammatory cytokine IL-32 are found in various tissues; their putative differences in biological function remain unknown. In the present study, we report that IL-32? is the most active isoform of the cytokine. Splicing to one less active IL-32? appears to be a salvage mechanism to reduce inflammation. Adenoviral overexpression of IL-32? (AdIL-32?) resulted in exclusion of the IL-32?-specific exon in vitro as well as in vivo, primarily leading to expression of IL-32? mRNA and protein. Splicing of the IL-32?-specific exon was prevented by single-nucleotide mutation, which blocked recognition of the splice site by the spliceosome. Overexpression of splice-resistant IL-32? in THP1 cells or rheumatoid arthritis (RA) synovial fibroblasts resulted in a greater induction of proinflammatory cytokines such as IL-1?, compared with IL-32?. Intraarticular introduction of IL-32? in mice resulted in joint inflammation and induction of several mediators associated with joint destruction. In RA synovial fibroblasts, overexpression of primarily IL-32? showed minimal secretion and reduced cytokine production. In contrast, overexpression of splice-resistant IL-32? in RA synovial fibroblasts exhibited marked secretion of IL-32?. In RA, we observed increased IL-32? expression compared with osteoarthritis synovial tissue. Furthermore, expression of TNF? and IL-6 correlated significantly with IL-32? expression in RA, whereas this was not observed for IL-32?. These data reveal that naturally occurring IL-32? can be spliced into IL-32?, which is a less potent proinflammatory mediator. Splicing of IL-32? into IL-32? is a safety switch in controlling the effects of IL-32? and thereby reduces chronic inflammation.

SUBMITTER: Heinhuis B 

PROVIDER: S-EPMC3064318 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature