Evidence for control of tumour necrosis factor-alpha (TNF-alpha) activity by TNF receptors in patients with proliferative diabetic retinopathy.
TNF-alpha has been implicated in the pathogenesis of insulin- dependent diabetes mellitus (IDDM). At present there are no studies linking serum levels of soluble TNF receptors (sTNF-R) to the development of diabetic microvascular complications such as proliferative diabetic retinopathy (PDR), or to the production of TNF-alpha in these patients. We investigated serum levels of sTNF receptors (sTNF-RI and sTNF-RII) in IDDM patients with or without PDR, and related these to the in vitro production of TNF-alpha upon activation of whole blood and isolated mononuclear cells (MNC). We observed higher serum levels of sTNF-RI in IDDM patients with active (range 945-6630 pg/ml; P = 0.029) or quiescent PDR (range 1675-4970 pg/ml; P = 0.00092) than in individuals with IDDM without retinopathy (range 657-2617 pg/ml) or healthy controls (range 710-1819 pg/ml; P = 0.0092 and 0.0023, respectively). Increased serum levels of sTNF-RII were also seen in IDDM patients with active PDR (range 1749-5218 pg/ml; P = 0.034) or quiescent PDR (range 1494-5249 pg/ml; P = 0.0084) when compared with disease controls (range 1259-4210 pg/ml) or healthy subjects (range 1237-4283 pg/ml). Whole blood production of biologically active TNF-alpha was lower in PDR patients than in disease (P = 0.04) and healthy controls (P < 0.005), contrasting with a higher production of TNF-alpha by lipopolysaccharide (LPS)-activated MNC from PDR patients (P = 0.013). Inhibition of TNF-alpha by TNF-R in plasma supernatants of activated blood from PDR patients was demonstrated by increase of TNF-alpha activity in the presence of anti-TNF-RI and anti-TNF-RII antibodies. These observations suggest that abnormalities in TNF-alpha production and control may operate during the development of microvascular complications of diabetes mellitus.
Limb
G A
GA
Department of Ophthalmology, St Thomas' Hospital, UMDS, London, UK.
Soomro
H
H
Janikoun
S
S
Hollifield
R D
RD
Shilling
J
J
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology; D003930:Diabetic Retinopathy / Q000097:blood / Q000209:etiology / Q000276:immunology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D015703:Antigens, CD; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha