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OtherIMMUNOPHARMACOLOGY

Hydroxyurea Induces the Gene Expression and Synthesis of Proinflammatory Cytokines In Vivo

Pierluigi Navarra, Ursula Grohmann, Giuseppe Nocentini, Giuseppe Tringali, Paolo Puccetti, Carlo Riccardi and Paolo Preziosi
Journal of Pharmacology and Experimental Therapeutics January 1997, 280 (1) 477-482;
Pierluigi Navarra
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Ursula Grohmann
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Giuseppe Nocentini
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Giuseppe Tringali
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Paolo Puccetti
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Carlo Riccardi
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Paolo Preziosi
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Abstract

The anticancer agent hydroxyurea (HU) was previously found to cause dose-dependent adrenal activation in the rat. The increased secretion of corticosterone (CORT) that results appeared to protect animals against HU toxicity, which was dramatically enhanced in adrenalectomized (ADX) rats. Similarities with the endocrine and toxicological profiles of proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF) led us to suggest that these effects of HU might be mediated by an increased synthesis of these cytokines. The goal of this study was therefore to demonstrate that HU induces the gene expression and synthesis of proinflammatory cytokinesin vivo. Intact and ADX rats were treated with HU, mRNA was extracted from spleen cells 2 and 24 hr after treatment and message levels for IL-1α, IL-2, IL-4, IL-6, TNFα and interferon-γ were evaluated using the reverse transcriptase-polymerase chain reaction technique. In some experiments, circulating levels of CORT and TNF were also measured. We found that transcripts of the proinflammatory cytokines, TNF, IL-6 and (though less clearly) IL-1α, were expressed in the majority of intact rats treated with HU but were absent or less evident in most controls. In contrast, gene expression of IL-2, IL-4 and interferon-γ was not influenced by drug treatment. Adrenalectomy markedly enhanced the effects of HU. Twenty-four hours after administration of the drug, the expression of TNF and IL-6 mRNAs was still higher in ADX rats compared with intact animals. Parallel measurements of plasma CORT levels revealed that gene expression of IL-1α and, to a lesser extent, TNF was inversely related to levels of circulating CORT. Adrenalectomy per se caused a significant increase in plasma TNF levels compared with intact controls. Hydroxyurea elicited significant increases in circulating TNF in both ADX and intact rats. These findings lend support to our working hypothesis and provide an explanation for both the rise in glucocorticoid secretion induced by HU in intact rats and the increase in lethality observed in animals with disruptions of the hypothalamo-pituitary-adrenal axis.

Footnotes

  • Send reprint requests to: Professor Paolo Preziosi, Institute of Pharmacology, Catholic University Medical School, Largo Francesco Vito 1, 00168 Rome, Italy.

  • ↵1 This study was supported by MURST Targeted Project “New Assessment Approaches in Toxicology” (1994/1995).

  • Abbreviations:
    HU
    hydroxyurea
    CORT
    corticosterone
    CRH
    corticotropin-releasing hormone
    HPA axis
    hypothalamo-pituitary-adrenal axis
    HYX rats
    hypophysectomized rats
    ADX rats
    adrenalectomized rats
    TNF
    tumor necrosis factor
    IL-1
    interleukin-1
    IL-2
    interleukin-2
    IL-4
    interleukin-4
    IL-6
    interleukin-6
    IL-12
    interleukin-12
    INF-γ
    interferon-γ
    HIV
    human immunodeficiency virus
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    EBSS
    Earle’s balanced salt solution
    • Received April 15, 1996.
    • Accepted September 23, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 1
1 Jan 1997
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OtherIMMUNOPHARMACOLOGY

Hydroxyurea Induces the Gene Expression and Synthesis of Proinflammatory Cytokines In Vivo

Pierluigi Navarra, Ursula Grohmann, Giuseppe Nocentini, Giuseppe Tringali, Paolo Puccetti, Carlo Riccardi and Paolo Preziosi
Journal of Pharmacology and Experimental Therapeutics January 1, 1997, 280 (1) 477-482;

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OtherIMMUNOPHARMACOLOGY

Hydroxyurea Induces the Gene Expression and Synthesis of Proinflammatory Cytokines In Vivo

Pierluigi Navarra, Ursula Grohmann, Giuseppe Nocentini, Giuseppe Tringali, Paolo Puccetti, Carlo Riccardi and Paolo Preziosi
Journal of Pharmacology and Experimental Therapeutics January 1, 1997, 280 (1) 477-482;
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