Decreased induction of IL-1beta in fibroblast-like synoviocytes: a possible regulatory mechanism maintaining joint homeostasis.
The response of fibroblast-like synoviocytes (FLS) to inflammatory stimuli was compared to their, respectively, derived dermal fibroblasts (DF) to determine whether regulatory controls exist within FLS to insure normal joint homeostasis. We further analyzed whether the loss of the normal regulatory controls present within the FLS could predispose to the development of non-rheumatic joint disease (non-RA). Primary fibroblast cell lines were generated from synovial and skin tissue from ten rheumatoid arthritis (RA) and ten non-RA patients. Cell lines were pulse labeled with [(35)S]-methionine and stimulated with TNFalpha or IL-1beta. Protein synthesis of IL-1beta, IL-6 and IL-8 was quantitated following immunoprecipitation. Gene expression was determined by Northern blot analysis. We noted, IL-1beta was minimally detected in FLS under nonstimulated conditions. In response to stimulation with IL-1beta or TNFalpha, production of IL-1beta was found to be 3.5 and 5-fold lower in FLS, respectively, when compared to DF from the same individual. In contrast, the production of IL-6 and IL-8 in FLS upon stimulation was 3-fold and 1.6-fold higher, respectively, than in DF. Furthermore, induced IL-1beta production in FLS, normalized relative to their, respectively, stimulated DF, was 2.5 times higher in non-RA versus RA-derived cells (p=0.032), an effect noted even after several passages of growth. Our data suggest that inductive expression of IL-1beta in FLS is under specific inhibitory control. Increased production of IL-1beta in FLS of susceptible individuals may lead to a higher risk of developing severe joint damage even in the absence of systemic inflammation.
Nadiv
Orna
O
Allergy and Immunology Institute, Assaf-Harofeh Medical Center, Zerifin, Israel.
Beer
Yiftah
Y
Goldberg
Michael
M
Agar
Gabriel
G
Loos
Michael
M
Katz
Yitzhak
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000032:analysis / Q000235:genetics*; D007596:Joints / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D013583:Synovial Membrane / Q000166:cytology* / Q000473:pathology
D053583:Interleukin-1beta