Expression of COX-2 and hsp72 in peritoneal macrophages after an acute ochratoxin A treatment in mice Maria Carmela Ferrante a , Marcella Bilancione a , Giuseppina Mattace Raso b , Emanuela Esposito b , Anna Iacono b , Annalisa Zaccaroni c , Rosaria Meli b, ⁎ a Department of Pathology and Animal Health, University of Naples Federico II, Naples, Italy b Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy c Department of Veterinary Public Health and Animal Pathology, University of Bologna, Italy Received 24 November 2005; accepted 27 March 2006 Abstract Ochratoxin A (OTA) is a secondary fungal metabolite produced by Aspergillus and Penicillium strains that elicits a broad spectrum of toxicological effects in animals and man. A single oral OTA administration (10 mg/kg) in mice induced after 24 h oxidative damage and polymorphonuclear leukocyte (PMN) infiltration in parenchymal organs. In fact, OTA treatment increased lipid peroxidation (via malondialdehyde formation) in kidney and liver and PMN accumulation in duodenum, as shown by myeloperoxidase activity. Following in vivo OTA treatment an increase of cyclooxygenase-2 and of heat shock protein 72 expression was evidenced in peritoneal macrophage lysates by Western blot. That OTA modulates these proteins involved in the inflammatory process indicates that the mycotoxin is able to activate immune cells. This study suggests that the oxidative stress, the neutrophil accumulation in parenchymal tissues and the modulation of inflammatory parameters in peritoneal macrophages induced by OTA are involved in its toxicity, and represent early events related to several aspects of OTA mycotoxicosis. © 2006 Elsevier Inc. All rights reserved. Keywords: Ochratoxin A; Cyclooxygenase-2; Heat shock protein 72; Peritoneal macrophage; Lipid peroxidation; Myeloperoxidase activity Introduction Ochratoxin A (OTA), a mycotoxin produced by various species of Aspergillus and Penicillium (Van Der Merwe et al., 1965), is a frequent contaminant of feed and foodstuffs (Speijers and Van Egmond, 1993). OTA induces progressive renal fibrosis, the Balkan endemic nephropathy (BEN), with impaired renal function and urinary tract tumours (Vrabcheva et al., 2004). In animals, this mycotoxin has been shown to induce a tubulo-interstitial nephropathy and inflammation similar to BEN, as well as renal adenoma and carcinoma (Kane et al., 1986; National Toxicology Program, 1989; Aukema et al., 2004). Animal studies indicate that OTA is a hepatic and cerebral toxin (Creppy et al., 1985; Belmadani et al., 1998), an immunomodulatory agent, often immunosuppressive (Singh et al., 1990; Politis et al., 2005; Harvey et al., 1992) and a potent teratogen (Wei and Sulik, 1993; Kuiper-Goodman and Scott, 1989). The chief mechanisms involved in OTA toxicity are the inhibition of protein synthesis and the induction of oxidative stress by lipid peroxidation and free radical formation, as described in rats and mammalian cells (Gillman et al., 1999; Hoehler et al., 1996, 1997; Rahimtula et al., 1988). Although toxic and carcinogenic effects of OTA are known, there have been very few, sometimes contrasting, reports on the mechanisms underlying immunotoxicity. Experimental studies indicate that OTA modulates the immune response even at levels far below the toxicity threshold (Müller et al., 1999). In rats, OTA reduces the bacteriolytic capability of macrophages (Alvarez et al., 2004); in mice, it suppresses the marrow granulocyte macrophage progenitors (Hong et al., 1988), induces lymphopenia, neutrophilia, eosinophilia, and inhibits antibody production (Müller et al., 1995, 2003) and Life Sciences 79 (2006) 1242 – 1247 www.elsevier.com/locate/lifescie ⁎ Corresponding author. Department of Experimental Pharmacology, via D. Montesano 49, 80131 Naples, Italy. Tel.: +39 81 678423; fax: +39 81 678403. E-mail address: meli@unina.it (R. Meli). 0024-3205/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2006.03.031