Regulation of the Kynurenine Pathway by IFN-γ in Murine Cloned Macrophages and Microglial Cells

  • D. Alberati-Giani
  • P. Ricciardi-Castagnoli
  • C. Köhler
  • A. M. Cesura
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 398)

Abstract

Several pieces of evidence indicate that, in neurological disorders associated with immune activation, brain infiltrating macrophages and microglial cells secrete various neurotoxic factors, such as glutamate and reactive oxygen species, which may greatly influence the survival of neurons (Mallat and Chamak, 1994; Giulian et al., 1993; Stone, 1993). Among the putative endogenous neurotoxins released by phagocytic cells during inflammatory processes, particular attention has been devoted to quinolinic acid (QUIN) (Heyes et al., 1993; Heyes, 1993). This tryptophan metabolite, formed along the kynurenine pathway, exerts its effect through activation of glutamate NMDA receptors and its accumulation within the CNS, observed in brain inflammatory disorders, has been speculatively linked to neuronal dysfunctions (Heyes et al., 1993). The overproduction of QUIN is mainly attributed to the induction of indoleamine-2,3 dioxygenase (IDO), the enzyme converting L-tryptophan into L-kynurenine (Takikawa et al., 1988; Taylor and Feng, 1991), by cytokines, such as IFN-γ. It has been found that IFN-γ activated human macrophages are able to produce QUIN directly from L-tryptophan (Heyes et al., 1992), whereas neurons and astroglial cells, even if they express inducible IDO activity (Saito et al., 1993a), do not appear to synthesise this neurotoxin directly from L-tryptophan. Whereas most of the available findings suggest that the large increase in QUIN cerebral levels in brain inflammatory conditions is mainly due to infiltrating activated macrophages, the relevance of activated microglial cells in the production of neuroactive kynurenines, has been only partially investigated (Saito et al., 1993a).

Keywords

Cysteine Pyruvate Dexamethasone Glucocorticoid Alanine 

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Copyright information

© Plenum Press, New York 1996

Authors and Affiliations

  • D. Alberati-Giani
    • 1
  • P. Ricciardi-Castagnoli
    • 2
  • C. Köhler
    • 1
  • A. M. Cesura
    • 1
  1. 1.Pharma DivisionPreclinical Research, Nervous System Diseases F. Hoffmann La Roche Ltd.BaselSwitzerland
  2. 2.CNR Center of CytopharmacologyUniversity of MilanMilanItaly

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