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

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Heinhuis B,Koenders MI,van de Loo FA,Netea MG,van den Berg WB,Joosten LA

doi

10.1073/pnas.1016005108

subject

Has Abstract

pub_date

2011-03-22 00:00:00

pages

4962-7

issue

eissn

0027-8424

issn

1091-6490

pii

1016005108

journal_volume

108

pub_type

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