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Title: Cytostasis is required for IL-1 induced nitric oxide production in transformed hamster fibroblasts.

Authors: Lavnikova, N; Lakhotia, A; Patel, N; Prokhorova, S; Laskin, D L

Published In J Cell Physiol, (1996 Dec)

Abstract: Interleukin-1 (IL-1) is known to inhibit proliferation in some tumor cells. This proinflammatory cytokine also induces nitric oxide production in a variety of cell types. In the present studies we determined if nitric oxide is involved in IL-1 induced growth inhibition in spontaneously transformed hamster embryonic fibroblasts (STHE cells). Both IL-1 alpha and IL-1 beta were found to stimulate nitric oxide production and to reduce 3H-thymidine (TdR) incorporation in high density cultures of STHE cells. However, maximal cytostasis was observed at least 24 h before significant amounts of nitric oxide accumulated in the cultures. In addition, doses of IL-1 which were too low to stimulate nitric oxide synthesis were effective in inducing cytostasis. Furthermore, in low density cultures of STHE cells, IL-1 inhibited DNA synthesis without inducing nitric oxide production. The nitric oxide synthase inhibitor NG-monomethyl-1-arginine (L-NMMA) had no effect on proliferation of cells plated at low density. In contrast, L-NMMA treatment resulted in a 40-60% reduction in IL-1 induced cytostasis in high density cultures. Neutralizing antibodies to IL-1 were found to completely block IL-1 induced cytostasis and nitric oxide production in cells plated at both densities. Although anti-IL-1 alpha and anti-IL-1 beta antibodies were highly specific and did not cross react, anti-tumor necrosis factor-alpha (TNF-alpha) antibody was able to partially suppress activation of STHE cells by both IL-1 alpha and IL-1 beta. These data suggest a potential involvement of endogenous TNF-alpha in IL-1 induced cytostasis and nitric oxide production. Exponentially growing STHE cells produced six-times less nitric oxide than non-proliferating cells. A ten-fold excess of 1-arginine was found to stimulate nitric oxide synthesis, an action that was independent of the rate of cellular proliferation. Taken together these data suggest that nitric oxide is not a major mediator of IL-1 induced cytostasis in STHE cells. Moreover, cytostasis appears to be required for nitric oxide synthesis in these cells.

PubMed ID: 8952702 Exiting the NIEHS site

MeSH Terms: Animals; Arginine/metabolism; Cell Division; Cell Transformation, Neoplastic/metabolism*; Cells, Cultured; Cricetinae; Cytokines/physiology; Dose-Response Relationship, Drug; Growth Inhibitors/pharmacology; Indomethacin/pharmacology; Interleukin-1/pharmacology*; Mesocricetus; Nitric Oxide/biosynthesis*; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; omega-N-Methylarginine/pharmacology

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