Abstract
Recent studies have suggested a role for aminoacid catabolites as important regulators of macrophage (M4) activities. We reported previously that picolinic acid (PA), a tryptophan catabolite produced under inflammatory conditions and a costimulus with IFNy of M4) effector functions, is a selective inducer of the M4 inflammatory protein-la (MIP-la) and -113 (MIPs), two CC-chemokines involved in the elicitation of the inflammatory reactions and in the development of the Thl responses. In this study, we have investigated the effects of IFNy on PA-induced MIPs expression and secretion by mouse M4) as well as the regulation of MIP-la/ß receptor, CCR5, by both stimuli alone or in combination. We demonstrated that IFNy inhibited MIPs mRNA stimulation by PA in a dose-and time-dependent fashion, despite its ability to induce other CC- or CXC chemokines. MIPs mRNA down-regulation was associated with decreased intracellular chemokine expression and secretion and was dependent on both mRNA destabilization and gene transcription inhibition. Moreover, IFNy inhibitory effects were stimulus-specific because MIPs induction by PA was either unaffected or increased by the anti-inflammatory cytokines, IL-10 and IL-4, or the pro-inflammatory stimulus, LPS, respectively. In contrast, we found that IFNy increased CCR5 basal expression, whereas PA down-regulated both constitutive and IFNy-induced CCR5 mRNA and protein levels. These results demonstrate that IFNy and PA have reciprocal effects on the production of MIPs chemokines and the expression of their receptor. The concerted action of IFNy and PA on MIP-la/ß chemokine/receptor system is likely to be of pathophysiological significance and to represent an important regulatory mechanism for leukocyte recruitment and distribution into damaged tissues during inflammatory responses.catabolites in AIDS, particularly of PA that, by upregulating MIPs expression, could exert protective effects on the host. This hypothesis is further supported by our most recent data showing that PA inhibits both constitutive and IFNy-induced CCR5 mRNA and protein expression on macrophages (manuscript in preparation).
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References
G. Melillo, M. C. Bosco, T. Musso, L. Varesio, Immunobiology of picolinic acid. In:Recent advances in tryptophan researchedited by G. Allegri Filippini, C.V.L. Costa, A.Bertazzo, (Plenum Press, New York, 1996), pp. 135–141.
W.T. Milton and F. Gensheng, Relationship between interferon-y, indoleamine 2,3-dioxygenase, and tryptophan catabolismFASEB J. 52516–2522 (1991).
R.R. Brown, Y. Ozaki, S.P. Datta, E.C. Borden, P.M. Sondel, D.G. Malone, Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDSAdv.Exp.Med.Biol. 294425–435 (1991).
L. Varesio, G. Cox, K. Pulkki, A. Brooks, G. Melillo, Arginineandtryptophan catabolism: the picolinic acid connection. In:Advances in tryptophan researchI. Ishiguro, R. Kido, T. Nagatsu, Y. Nagamura, Y. Ohta, Eds. (Fujita Health University Press, Tokyo, Japan, 1992)pp.309–314.
W. Dai and S.L. Gupta, Molecular cloning, sequencing and expression of human interferon-y-inducible indoleamine 2,3-dioxigenase cDNABiochem.Biophys.Res.Commun. 1681–9 (1990).
Y. Ozaki, M.P. Edelstein, D.S. Duch, Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon-gammaProc.Natl.Acad.Sci.USA 851242–1249 (1988).
J.M. Carlin, E.C. Borden, G.L. Byrne, Interferon-induced indoleamine 2,3-dioxigenase activity inhibitsClamydia psittacireplication in human macrophagesJ.Interferon Res. 9329–335 (1999).
E.R. Pfefferkom, Interferon-gamma blocks the growth ofToxoplasma gondiiin human fibroblasts by inducing the host cells to degrade tryptophanProc.Natl.Acad.Sci.USA 81908–916 (1984).
T.F. Pais and R. Appelberg, Macrophage control of mycobacterial growth induced by picolinic acid is dependent on host cell apoptosisJ.Immunol. 164389–397 (2000).
H.W. Murray, A. Szuro-Sudol, D. Wellner, M.J. Oca, A.M. Granger, D.M. Libby, C.D. Rothermel, B.J. Rubin, Role of tryptophan degradation in respiratory burst-independent antimicrobial activity of gamma interferon-stimulated human macrophages/nfect./mmun.57, 845–850 (1989).
L. Varesio, A. Soleti, D. Radzioch, K. Putkki, A. Brooks, G.L. Gusella, M.C. Bosco, G.Fomi, Picolinic acid and its influence on the immune system. In:L-tryptophan current prospects in medicine and drug safety.H. S. Walter Kochen, Ed. (Walter de Gruyter, Berlin, New York, 1994), pp. 99–110.
L. Varesio, L. Espinoza-Delgado, L. Gusella, G.W. Cox, G. Melillo, T. Musso, M.C. Bosco, Role of cytokines in the activation of monocytes. In:Human cytokines: their role in disease and therapy.B. B. Aggarwal and R. K. Puri, Eds. (Blackwell Scientific Publication, Inc., Cambridge, MA, 1995), pp. 55–69.
D.H. Munn, E. Shafizadeh, J.T. Attwood, I. Bondarev, A. Pashine, A.L. Mellor, Inhibition of T cell proliferation by macrophage tryptophan catabolismJ.Exp.Med.189, 1363–1372 (1999).
K.M. Kopydlowski, C.A. Salkowski, M.J. Cody, N. Van Rooijen, J. Major, T.A. Hamilton, S.N. Vogel. Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivoJ.Immunol.163, 1537–1544 (1999).
M.M. Shi, J. J. Godleski, J.D. Paulauskis. Regulation of macrophage inflammatory protein -1 alpha mRNA by oxidative stressJ.Biol.Chem.271, 5878–5883 (1996).
D.M. Paulnock, K.P. Demick, S.P. Coller. Analysis of interferon-gamma-dependent and-independent pathways of macrophage activationJ.Leukoc.Biol. 67677–682 (2000).
A. Mehler Formation of picolinic and quinolinic acids following enzimatic oxidation of 3- hydroxyanthranilate to quinolateJ.Biol.Chem. 218241–250 (1956).
T. Rebello, B. Lonnerdal, L. Hurley, Picolinic acid in milk, pancreatic juice and intestine:inadequate for role in zinc absorpionAm.J.Clin.Nutr. 351–9 (1982).
G.W. Evans and P. E. Johnson, Characterization and quantitation of a zinc binding ligand in human milkPediatr.Res. 14867–871 (1980).
C. Dazzi, G. Candiano, S. Massazza, A. Ponzetto, L. Varesio, New high-performance liquid chromatografy method for the detection of picolinic acid in biological fluidsJ.Chromatogr.B751, 61–68 (2001).
L. Varesio, M. Clayton, E. Blasi, R. Ruffmann, D. Radzioch, Picolinic acid, a catabolite of L-tryptophan, as the second signal in the activation of IFN-gamma primed macrophagesJ.Immunol. 1454265–4272 (1990).
G. Melillo, G. Cox, A. Biragyn, L. Sheftler, L. Varesio, Regulation of nitric oxide synthase mRNA expression by interferon-gamma and picolinic acidJ.Biol.Chem. 2698128–8135 (1994).
R. Ruffmann, R. Schlick, M. Chingos, W. Budzynsky, L. Varesio, Antiproliferative activity of picolinic acid due to macrophage activationDrugs.Exp.Clin.Res. 13607–611 (1987).
J. Fernandez-Pol, V. Bono, G. Johnson, Control of growth by picolinic acid: differential response of normal and transformed cellsProc.Natl.Acad.Sci.USA7, 2889–2895 (1977).
J. Plowman, S.D. Harrison, D. Dykes, K.D. Paull, V.L. Narayanan, H.K. Tobol, J. Martin, D.P. Griswold, Preclinical antitumor activity of an a-picoline derivate, penclomedine (NSC 388720), on human and murine tumorsCancer Res 491909–1915 (1989).
S.W. Leuthauser, L.W. Oberley, T.D. Oberley, Antitumor activity of picolinic acid in CBA/J miceJ.Natl.Cancer Inst 68123–129 (1982).
E. Blasi, R. Mazzolla, L. Pitzurra, R. Barluzzi, F. Bistoni, Protective effect of picolinic acid on mice intracerebrally infected with lethal doses ofCandida albicans Antimicrob. Agents Chemother37, 2422–2426 (1993).
E. Blasi, D. Radzioch, L. Varesio, Inibition of retroviral mRNA expression in the murine macrophage cell line GG2EE by biologic response modifiersJ./mmunol. 1412153–2160 (1988).
G. Melillo, T. Musso, A. Sica, L. S. Taylor, G. Cox, L. Varesio, A hypoxia responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoterJ.Exp.Med. 1821683–1693 (1995).
G. Melillo, G. Cox, D. Radzioch, L. Varesio, Picolinic acid, a catabolite of L-tryptophan, is a costimulus for the induction of reactive nitrogen intermediate production in murine macrophagesJ.Immunol. 1504031–4039 (1993).
C.F. Nathan and J.B. Hibbs, Role of nitric oxide synthesis in macrophage antimicrobial activityCurr.Opin.lmmunol. 365–70 (1991).
T. Springer, Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigmCell76, 301–314 (1994).
A. Ben-Baruk, D. Michiel, J. Oppenheim, Signals and receptor involved in the recruitment of inflammatory cellsJ.Biol.Chem.270, 11703–11706 (1995).
M. Baggiolini, B. Dewald, B. Moser, Interleukin 8 and related chemotactic cytokines: CXC and CC chemokinesAdv.Immunol.55, 97–179 (1994).
T. Schall, Biology of RANTES/SIS cytokine familyCytokine3, 165–183 (1991).
P. Murphy, Chemokine receptors: structure, functions and role in microbial pathogenesisCytokine Growth Factor Rev. 747–53 (1996).
M. Miller and M. Krangel, Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokinesCrit.Rev.Immunol. 1217–46 (1992).
D. Taub, T.J. Sayers, C.R.D. Carter, J. Ortaldo, a and 13 chemokines induce NK cell migration and enhance NK-mediated cytolysisJ.Immunol. 1553877–3888 (1995).
J.T. Siveke and A. Hamann, Cutting edge: T helper-1 and T helper-2 cells respond differentially to chemokinesJ.Immunol. 160550–554 (1998).
M.R. HortonM.D.Burdick, R. Strieter, C. Bao, P.W. Noble, Regulation of Hyaluronan-induced chemokine gene expression by IL-10 and IFN-gamma in mouse macrophagesJ.Immunol. 1603023–3030 (1998).
M.C. Bosco, A. Rapisarda, S. Massazza, G. Melillo, H. Young, L. Varesio, The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage-inflammatory protein-la and -l3 in macrophagesJ.Immunol. 1643283–3291 (2000).
W.J. Karpus, N.W. Lukacs, B.L. McRae, R. Strieter, S. Kunkel, S.D. Miller, An important role for the chemokine macrophage inflammatory protein-la in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitisJ.Immunol. 1555003–5010 (1995).
F. Sallusto, A. Lanzavecchia, C.R. Mackay, Chemokines and chemokine receptors in T-cell priming and Thl/Th2-mediated responsesImmunol.Today 19568–574 (1998).
D. Taub, K. Conlon, A. Lloyd, J. Oppenheim, D. Kelvin, Preferential migration of activated CD4’ and CD8’ T cells in response toMIP-laand MIP-1(3Science 260355–358 (1993).
L.A. DiPietro, M.D. Burdick, Q.E. Low, S. Kunkel, R. StrieterMIP-lalphaas a critical macrophage chemoattractant in murine wound repairJ.Clin.Invest. 1011693–1698 (1998).
A. Rot, M. Krienger, T. Brunner, S. Bischoff, T. Shall, C. Dahinden, RANTES and macrophage protein la induce the migration and activation of normal human eosinophil granulocytesJ.Exp.Med. 1761489–1495 (1992).
D. Cook The role of MIP-1 alpha in inflammation and hematopoiesisJ.Leukoc.Biol. 5961–66 (1996).
S. Schrum, P. Probst, B. Fleischer, P.F. Zipfel, Synthesis of the CC-chemokines MIP-la, M1P-1 3, and RANTES is associated with a type 1 immune responseJ.Immunol. 1573598–3603 (1996).
D. Alberati-Giani, P. Malherbe, P. Ricciardi-Castagnoli, C. Kohler, S. Denis-Donini, A.M. Cesura, Differential regulation of indoleamine 2,3-dioxygenase expression by nitric oxide and inflammatory mediators in IFN-gamma-activated murine macrophages and microglial cellsJ.Immunol. 159419–426 (1997).
J. Fernandez-Pol, Iron: possible cause of the GI arrest induced by picolinic acidBiochem Biophys Res Commun 78136–141 (1977).
G. Melillo, B. Taylor, A. Brooks, T. Musso, G. Cox, L. Varesio, Functional requirement of the hypoxia responsive element in the activation of the inducible nitric oxide synthase promoter by iron chelator desferrioxamineJ. Biol.Chem. 27212236–12243 (1996).
P. Giardina and R. Grady, Chelation therapy in beta-thalassemia: the benefits and limitation of desferrioxamineSemin.Hematol. 32304–3I2 (1995).
N. Mukaida, Y. Mahe, K. Matsushima, Cooperative interaction of nuclear factor-KB- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by prointlammatory cytokinesJ.Biol.Chem. 26521128–21133 (1990).
A. J. Valente, J. Xie, M. Abramova, U. Wenzel, H. Abbound, D. Graves. A complex element regulates IFNgamma-stimulated monocyte chemoattractant protein-1 gene transcription.J.Immunol. 1613719–3728, 1998.
M. Baggiolini and C. Dahinden, CC chemokines in allergic inflammationImmunol.Today 15127–133 (1994).
Z. Brown, R. Robson, J. Westwick, Regulation and expression of chemokines: potential role in glomerulonephritisJ.Leukocyte Biol. 5975–80 (1996).
M.J.Cameron, G.A. ArreazaM.Grattan, C. Meagher, S.Sharif, M.D.Burdick, Strieter R, Cook D, T.L. Delovitch, Differential expression of CC-chemokines and the CCR5 receptor in the pancreas is associated with progression to type [diabetesJ.Immunol. 1651102–1110 (2000).
S. Gautam, J. M. Tebo, T. Hamilton, IL-4 suppresses cytokine gene expression induced by IFN-y and/or IL-2 in murine peritoneal macrophagesJ.Immunol. 1481725–1732 (1992).
C. Bogdan, Y. Vodovotz, C. Nathan, Macrophage deactivation by interleukin 10JExp.Med. 1741549–1554 (1991).
Y. Ohmori and T. Hamilton, IFN-gamma selectively inhibits lipopolysaccharide-inducible JE/monocyte chemoattractant protein-1 and KC/GRO/melanoma growth-stimulating activity gene expression in mouse peritoneal macrophagesJ.Immunol. 1532204–2212 (1994).
R. Bonecchi, S. Sozzani, J.T. Stine, W. Luini, G. D’Amico, P. AllavenaD.Chantry, A. Mantovani. Divergent effects of interleukin-4 and interferon-gamma on macrophage-derived chemokine (MDC) production: an amplification circuit of polarized T helper-2 responsesBlood 982668–2671 (1998).
U. Boehm, T. Klamp, M. Groot, J. Howard, Cellular responses to interferon-gammaAnnu.Rev.Immunol. 15749–795 (1997).
Y. Ohmori and T. Hamilton, The interferon-stimulated response element and a KB site mediate synergistic induction of murineIP-10gene transcription by IFN-y and TNF-aJImmunol. 1545235–5239 (1995).
E. Blasi, D. Bauer, R. Barluzzi, R. Mazzolla, F. Bistoni, Pattern of cytokine gene expression in brains of mice protected by picolinic acid against lethal intracerebral infection withCandida albicans J.Neuroimmunol. 52205–213 (1994).
W.J. Karpus and R. Ransohoff, Cutting edge commentary:chemokine regulation of experimental autoimmune encephalomyelitis: temporal and spatial expression patterns govern disease pathogenesisJImmunol.161, 2667–2671 (1998).
A.E. Koch, S. Kunkel, L.A. Harlow, D.D. Mazarakis, G.K. Haines, M.D. Burdick, R.M. Pope, R. Strieter, Macrophage inflammatory protein-lalpha: a novel chemotactic cytokine for macrophages in rheumatoid arthritisJ.Clin.lnvest. 93921–929 (1994).
F. Cocchi, A. Devico, A. Garzino-Demo, S. Arya, R. Gallo, P. Lusso. Identification of RANTES, MIP la and MIP lß as the major HIV-suppressive factors produced by CD8’ T cells.Science 2701811–1815, 1995.
G. Alkhatib, C. Combadiere, C. C. Broder, Y. Feng, P. E. Kennedy, P. Murphy, E. A. Berger. CC CKR5: a RANTES, MIP-lalphaMIP-1 betareceptor as a fusion cofactor for macrophage-tropic HIV-1.Science 2721955–1958, 1996.
H. Schmidtmayerova, S. L. H. Nottet, G. Nuovo, T. Raabe, C. R. Flanagan, L. Dubrovsky, H. E. Gendelman, A. Cerami, M. Bykrinsky, B. Sherry. Human immunodeficiency virus type 1 infection alters chemokine f3 peptide expression in human monocytes: implication for recruitment of leukocytes into brain and lymph nodes.Proc.Natl.Acad.Sci. USA 93700–709, 1996.
D. Fuchs, A. Forsman, L. Hagberg, M. Larsson, G. Norkrans, G. ReibneggerE.R. Werner, H. Wachter. Immune activation and decreased tryptophan in patients with HIV-1 infection.J.Interferon Res. 10599–605, 1990.
C. L. Achim, M. P. Heyes, C. A. Wiley. Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brain.J.Clin.lnvest. 912769–2775, 1993.
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Bosco, M.C., Rapisarda, A., Reffo, G., Massazza, S., Pastorino, S., Varesio, L. (2003). Macrophage Activating Properties of The Tryptophan Catabolite Picolinic Acid. In: Allegri, G., Costa, C.V.L., Ragazzi, E., Steinhart, H., Varesio, L. (eds) Developments in Tryptophan and Serotonin Metabolism. Advances in Experimental Medicine and Biology, vol 527. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0135-0_6
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