IL-17 regulates gene expression and protein synthesis of the complement system, C3 and factor B, in skin fibroblasts.
Human IL-17 is a cytokine secreted by CD4+-activated memory T cells with the profile of effects of a Th1 cytokine. The effects of IL-17 on many cellular constituents of joints suggest that it may participate in inflammatory joint diseases. Proteins of the complement system are known to be regulated by pro- and anti-inflammatory cytokines. The purpose of this work was to study the effect of IL-17 alone and combined with tumour necrosis factor (TNF) on the expression and synthesis of factor B and C3. Fibroblasts were stimulated with the relevant cytokine or cytokines, pulse labelled with 35S-methionine, and the newly synthesized proteins were immunoprecipitated and subjected to SDS-PAGE. Gene expression was determined by Northern blot analysis. IL-17 10 ng/ml induced increases in gene expression and protein synthesis of C3, 2.25 +/- 0.26- and 2.7 +/- 0.7-fold, respectively with concomitant non-significant effects on factor B, 1.5 +/- 0.45- and 2.2 +/- 1. 2-fold, respectively. When both IL-17 and TNF were present simultaneously, the synthesis of factor B increased by 85% more than the expected additive effects of these cytokines separately, while for C3 the effect of both cytokines was 19% lower than the expected additive effect (observed/expected = 0.81). IL-4 reduced the synergistic effect by 50%. We conclude that IL-17 has a regulatory role on C3 expression and synthesis and an amplifying effect on TNF-induced factor B synthesis. Taken together with the evidence that TNF is a major cytokine involved in the inflammation of rheumatoid arthritis, it suggests that IL-17 has a proinflammatory role in the inflammation process of joints. The distinct effects of IL-4, IL-17 and TNF on the synthesis of factor B in fibroblasts suggest that factor B and the alternative pathway of the complement system may play an important role in joint inflammation.
Katz
Y
Y
Allergy and Immunology Institute, 'Assaf-Harofeh' Medical Centre, Zerifin, and Department of Paediatrics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Nadiv
O
O
Rapoport
M J
MJ
Loos
M
M
D000293:Adolescent; D000328:Adult; D002460:Cell Line; D003176:Complement C3 / Q000096:biosynthesis* / Q000235:genetics; D011415:Complement Factor B / Q000096:biosynthesis* / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D008875:Middle Aged; D010452:Peptide Biosynthesis / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012867:Skin / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D003176:Complement C3; D020381:Interleukin-17; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D003165:Complement System Proteins; D011415:Complement Factor B