Laboratory Investigation

Kidney International (1990) 37, 767–775; doi:10.1038/ki.1990.44

Interleukin 1-alpha and tumor necrosis factor-alpha induce oxygen radical production in mesangial cells

Heinfried H Radeke1, Beate Meier1, Nicholas Topley1, Jürgen Flöge1, Gerhard G Habermehl1 and Klaus Resch1

1Department of Molecular Pharmacology, Medical School, Konstanty-Gutschow-Str. 8 and Department of Chemistry, Veterinary School, Bischofsholer Damm 15, D-3000 Hannover, Federal Republic of Germany

Correspondence: Dr med Heinfried H Radeke, Department of Molecular Pharmacology, Medical School, Konstanty-Gutschow-Str. 8, D-3000 Hannover 61, Federal Republic of Germany.

Received 15 May 1989; Revised 31 August 1989; Accepted 6 September 1989.

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Abstract

Interleukin 1-alpha and tumor necrosis factor-alpha induce oxygen radical production in mesangial cells. Adherent human mesangial cells (HMC) were unable to phagocytose serum-treated zymosan (STZ), nevertheless this stimulus (1 mg/ml) induced a marked immediate increase of H2O2 and O2- release at a rate of 3.15 plusminus 0.35 and 3.40 plusminus 0.12 nmol/106 HMC/hr, respectively. Zymosan alone resulted in no release of either H2O2 or O2-. Phorbol myristate acetate (PMA, 2 times 10-6 M) had only marginal effects on HMC leading to the generation of 0.273 plusminus 0.014 nmol O2-/106 HMC/hr. After a lag period, human recombinant tumor necrosis factor-alpha (TNF-alpha) and human recombinant interleukin 1-alpha (IL-1alpha) both induced significant O2- production measured as SOD inhibitable reduction of cytochrome c, 5 times 10-5 M, by adherent HMC for up to five hours, the maximum rates being 3.04 plusminus 0.08 and 3.2 plusminus 0.08 nmol/106 HMC/hr for IL-1alpha and TNF-alpha, respectively. Significant O2- release was detectable at 0.625 ng/ml (37 pM) IL-1alpha or 1 ng/ml (59 pM) TNF-alpha (P < 0.05). Catalase inhibitable H2O2 production was also induced by IL-1alpha and TNF-alpha in a dose dependent manner. Using scopoletin (40 nM) and 1 microM peroxidase we fluorimetrically measured 1.73 plusminus 0.14 and 1.49 plusminus 0.19 nmol H2O2/106 HMC/hr induced by IL-1alpha (25 ng/ml) and TNF-alpha (20 ng/ml). Finally, we ascertained the type of radical species produced by HMC stimulated by cytokines employing ESR-spin-trapping with DMPO. These results demonstrated that O2- was the primary radical species formed. We have thus established for the first time that HMC are able to generate significant oxygen radicals in response to IL-1alpha and TNF-alpha, in amounts comparable to that produced by monocytes. These findings may be relevant to the pathogenesis of human glomerulonephritis.

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