TY - JOUR

T1 - The pharmacokinetics, distribution and degradation of human recombinant interleukin 1 beta in normal rats

AU - Wogensen, L D

AU - Welinder, B

AU - Hejnaes, K R

AU - Poulsen, Steen Seier

AU - Nilsson, P

AU - Nerup, J

PY - 1991/11

Y1 - 1991/11

N2 - Based upon in vivo rat experiments it was recently suggested that interleukin 1 in the circulation may be implicated in the initial events of beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half-lives of distribution (T1/2 alpha) and elimination phases (T1/2 beta) of human recombinant interleukin 1 beta (rIL-1 beta), and its tissue distribution and cellular localization by means of mono-labelled, biologically active 125I-rIL-1 beta. After intravenous (i.v.) injection, 125I-rIL-1 beta was eliminated from the circulation with a T1/2 alpha of 2.9 min and a T1/2 beta of 41.1 min. The central and peripheral volume of distribution was 20.7 and 19.1 ml/rat, respectively, and the metabolic clearance rate was 16.9 ml/min/kg. The kidney and liver showed the highest accumulation of tracer, and autoradiography demonstrated that 125I-rIL-1 beta was localized to the proximal tubules in the kidney and to the hepatocytes in the liver. Furthermore, grains were localized to the islets of Langerhans in the pancreas. Tracer-bound proteins corresponding to intact 125I-rIL-1 beta were found in the circulation after i.v., intraperitoneal (i.p.) and subcutaneous (s.c.) injections, as demonstrated by high performance size exclusion chromatography, trichloracetic acid precipitation and SDS-PAGE until 5 h after tracer injection. Pre-treatment with 'cold' rIL-1 beta enhanced degradation of a subsequent injection of tracer. The route of administration was of importance for the biological effects of rIL-1 beta, as demonstrated by a reduced food intake, increased rectal temperature and blood glucose after s.c. injection of rIL-1 beta compared with i.p. The present demonstration of intact rIL-1 beta in the circulation and the islets of Langerhans supports the hypothesis that systemic IL-1 beta may be involved in the initial beta-cell destruction leading to IDDM in humans.

AB - Based upon in vivo rat experiments it was recently suggested that interleukin 1 in the circulation may be implicated in the initial events of beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) in humans. The aim of the present study was to estimate half-lives of distribution (T1/2 alpha) and elimination phases (T1/2 beta) of human recombinant interleukin 1 beta (rIL-1 beta), and its tissue distribution and cellular localization by means of mono-labelled, biologically active 125I-rIL-1 beta. After intravenous (i.v.) injection, 125I-rIL-1 beta was eliminated from the circulation with a T1/2 alpha of 2.9 min and a T1/2 beta of 41.1 min. The central and peripheral volume of distribution was 20.7 and 19.1 ml/rat, respectively, and the metabolic clearance rate was 16.9 ml/min/kg. The kidney and liver showed the highest accumulation of tracer, and autoradiography demonstrated that 125I-rIL-1 beta was localized to the proximal tubules in the kidney and to the hepatocytes in the liver. Furthermore, grains were localized to the islets of Langerhans in the pancreas. Tracer-bound proteins corresponding to intact 125I-rIL-1 beta were found in the circulation after i.v., intraperitoneal (i.p.) and subcutaneous (s.c.) injections, as demonstrated by high performance size exclusion chromatography, trichloracetic acid precipitation and SDS-PAGE until 5 h after tracer injection. Pre-treatment with 'cold' rIL-1 beta enhanced degradation of a subsequent injection of tracer. The route of administration was of importance for the biological effects of rIL-1 beta, as demonstrated by a reduced food intake, increased rectal temperature and blood glucose after s.c. injection of rIL-1 beta compared with i.p. The present demonstration of intact rIL-1 beta in the circulation and the islets of Langerhans supports the hypothesis that systemic IL-1 beta may be involved in the initial beta-cell destruction leading to IDDM in humans.

KW - Animals

KW - Autoradiography

KW - Half-Life

KW - Interleukin-1

KW - Iodine Radioisotopes

KW - Male

KW - Metabolic Clearance Rate

KW - Protein Binding

KW - Rats

KW - Rats, Inbred Strains

KW - Recombinant Proteins

KW - Tissue Distribution

KW - Tumor Necrosis Factor-alpha

M3 - Journal article

C2 - 1947795

VL - 34

SP - 597

EP - 610

JO - Scandinavian Journal of Immunology, Supplement

JF - Scandinavian Journal of Immunology, Supplement

SN - 0301-6323

IS - 5

ER -