Differential regulation of tumour necrosis factor receptors (TNF-R) by IL-4; upregulation of P55 and P75 TNF-R on synovial joint mononuclear cells.
Interleukin 4 (IL-4) has previously been shown to downregulate the production of proinflammatory cytokines such as TNF-alpha, and hence has been considered to be a potential anti-inflammatory agent. In this study we have investigated the effects of IL-4 on the expression of both p55 and p75 TNF receptors (TNF-R) by flow cytometry and radioligand binding analyses and demonstrate that IL-4 downregulates both p55 and p75 TNF-R on HeLa and Jijoye cell lines in a dose dependent manner. IL-4 reduced the number of p55 TNF-R on HeLa cells from 6400 (Kd 5.1 nM) to 3900 (Kd 3.7 nM), and p75 TNF-R on Jijoye cells from 4800 (Kd 1.6 nM) to 3250 (Kd 1.5 nM). However, different effects were observed on peripheral blood mononuclear cells (PBMC). IL-4 inhibited the increase in p55 and p75 TNF-R on PBMC following adherence, whereas IL-4 upregulated p75 TNF-R expressed on PHA induced T cell blasts. To assess further the possible anti-inflammatory properties of IL-4, we studied its effects on synovial joint mononuclear cell cultures from 15 patients with inflammatory synovitis. In contrast to the differential effects of IL-4 on monocytes and T cells, IL-4 upregulated both p55 (P < 0.05) and p75 TNF-R (P < 0.005) on synovial joint cells in culture. IL-4 treatment caused a small decrease in levels of bioactive TNF-alpha in RA synovial culture supernatants, together with an increase in soluble p75 TNF-R levels although differences were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Cope
A P
AP
Kennedy Institute of Rheumatology, Hammersmith, London.
Gibbons
D L
DL
Aderka
D
D
Foxwell
B M
BM
Wallach
D
D
Maini
R N
RN
Feldmann
M
M
Brennan
F M
FM
D001168:Arthritis / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002051:Burkitt Lymphoma; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D007719:Knee Joint; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000302:isolation & purification / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013582:Synovial Fluid / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4