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SUMMARY Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis where formyl peptides, which are cleavage products of bacterial and mitochondrial proteins, are present. In this study, we demonstrated that interferon gamma (IFN)-γ and interleukin (IL)-10 induced the overexpression of the receptor for the Fc portion of IgG I (Fcγ RI) in monocytes from tuberculosis (TB) patients, showing that these cells respond to IFN-γ and IL-10 signals. We also demonstrated that lower doses of IL-10 render monocytes from TB patients less responsive to higher doses of the cytokine. Although the prototypic formyl peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a well-known proinflammatory agonist, we have demonstrated previously that preincubation of monocytes with FMLP inhibited the up-regulation of Fcγ RI induced by IFN-γ or IL-10. This effect was not observed in monocytes from TB patientes. FMLP also induced the down-regulation of the expression of Fcγ RI in monocytes that had been activated already with IFN-γ . However, this effect of FMLP was not observed in monocytes from TB patients and supernatants from monocytes obtained from these patients were incapable of inducing the down-regulation of Fcγ RI. In contrast to normal donors, supernatants from FMLP-treated neutrophils from TB patients did not modify the basal level of expression of Fcγ RI in monocytes from normal donors. In conclusion, in this study we demonstrated the existence of two novel mechanisms that may contribute to the pathological effects generated by M. tuberculosis: the enhancement of Fcγ RI in response to IFN-γ and IL-10, and the unresponsiveness to the anti-inflammatory effects induced by formyl peptides. [ABSTRACT FROM AUTHOR]

Abstract N -Formyl peptides are cleavage products of bacterial and mitochondrial proteins that have pro-inflammatory activities and play an important role in antibacterial host defence. FcγRI is a receptor for the Fc portion of immunoglobulin G expressed in monocytes that mediates cytotoxicity and is upregulated by interferon-γ (IFN-γ) and interleukin-10 (IL-10). In this report, we demonstrate that N -formyl-methionyl-leucyl-phenylalanine (FMLP) downregulates the expression of FcγRI in IFN-γ-treated monocytes, but not in IL-10-treated monocytes. We determine that supernatants obtained from monocytes treated with IFN-γ and then exposed to FMLP induce the downregulation of FcγRI in naïve monocytes. This effect is abrogated by the protease inhibitors phenylmethylsulphonyl fluoride and phosphoramidon, which inhibit serine and metalloproteases, respectively. Supernatants from FMLP-treated neutrophils also induce the downregulation of FcγRI, when added to naïve monocytes. Similar observations were obtained in vivo in a mouse model of chronic inflammation. In vivo , FMLP also downregulates the expression of FcγRs in IFN-γ-activated macrophages. Our results support the existence of a new mechanism through which FMLP could modulate the activity of monocytes/macrophages during bacterial infections. [ABSTRACT FROM AUTHOR]