Human Alveolar Macrophages and Granulocyte-macrophage Colony-stimulating Factor-induced Monocyte-derived Macrophages Are Resistant to H2O2 via Their High Basal and Inducible Levels of Catalase Activity

Human alveolar macrophages (A-MΦ) and macrophages (MΦ) generated from human monocytes under the influence of granulocyte-macrophage colony-stimulating factors (GM-MΦ) express high levels of catalase activity and are highly resistant to H2O2. In contrast, MΦ generated from monocytes by macrophage colony-stimulating factors (M-MΦ) express low catalase activity and are about 50-fold more sensitive to H2O2 than GM-MΦ or A-MΦ. Both A-MΦ and GM-MΦ but not M-MΦ can induce catalase expression in both protein and mRNA levels when stimulated with H2O2 or zymosan. M-MΦ but not GM-MΦ produce a large amount of H2O2 in response to zymosan or heat-killed Staphylococcus aureus. These findings indicate that GM-MΦ and A-MΦ but not M-MΦ are strong scavengers of H2O2 via the high basal level of catalase activity and a marked ability of catalase induction and that catalase activity of MΦ is regulated by colony-stimulating factors during differentiation. Human alveolar macrophages (A-MΦ) and macrophages (MΦ) generated from human monocytes under the influence of granulocyte-macrophage colony-stimulating factors (GM-MΦ) express high levels of catalase activity and are highly resistant to H2O2. In contrast, MΦ generated from monocytes by macrophage colony-stimulating factors (M-MΦ) express low catalase activity and are about 50-fold more sensitive to H2O2 than GM-MΦ or A-MΦ. Both A-MΦ and GM-MΦ but not M-MΦ can induce catalase expression in both protein and mRNA levels when stimulated with H2O2 or zymosan. M-MΦ but not GM-MΦ produce a large amount of H2O2 in response to zymosan or heat-killed Staphylococcus aureus. These findings indicate that GM-MΦ and A-MΦ but not M-MΦ are strong scavengers of H2O2 via the high basal level of catalase activity and a marked ability of catalase induction and that catalase activity of MΦ is regulated by colony-stimulating factors during differentiation. alveolar macrophages macrophage(s) colony-stimulating factor(s) granulocyte-macrophage colony-stimulating factor, GM-MΦ, GM-CSF-induced macrophages macrophage colony-stimulating factor M-CSF-induced macrophages reactive oxygen species human erythrocyte catalase human immunodeficiency virus, type I Human alveolar macrophages (A-MΦ)1 can survive for a long duration (1Thomas E.D. Ramberg R.E. Sale G.E. Sparkes R.S. Golde D.W. Science. 1976; 192: 1016-1018Crossref PubMed Scopus (262) Google Scholar, 2van oud Alblas A.B. van Furth R. J. Exp. Med. 1979; 149: 1504-1518Crossref PubMed Scopus (224) Google Scholar, 3Marques L.J. Teschler H. Guzman J. Costabel U. Am. J. Respir. Crit. Care Med. 1997; 156: 1700-1702Crossref PubMed Scopus (38) Google Scholar, 4Nakata K. Gotoh H. Watanabe J. Uetake T. Komuro I. Yuasa K. Watanabe S. Ieki R. Sakamaki H. Akiyama H. Kudoh S. Naitoh M. Satoh H. Shimada K. Blood. 1999; 93: 667-673Crossref PubMed Google Scholar) to exposure to not only chemical pollutants and exogenous oxidants but also inflammatory mediators and endogenously generated reactive oxygen species (ROS) and play important roles in phagocytosis-mediated host defense against microbial infection via the airway (5Rossi F. Biochim. Biophys. Acta. 1986; 853: 65-89Crossref PubMed Scopus (587) Google Scholar, 6Sibille Y. Reynolds H.Y. Am. Rev. Respir. Dis. 1990; 141: 471-501Crossref PubMed Scopus (936) Google Scholar). Superoxide dismutase, catalase, and glutathione are the main cellular ROS-degrading enzyme systems; superoxide dismutase converts superoxide radical (O⨪2) into H2O2, which is metabolized by catalase and glutathione peroxidase. Previous studies indicated that these enzymes are abundant in A-MΦ (7Zeidler R.B. Flynn J.A. Arnold J.C. Conley N.S. Inflammation. 1987; 11: 371-379Crossref PubMed Scopus (10) Google Scholar, 8Duran H.A. Giulivi C. Boveris A. De Rey B.M. Cell. Mol. Biol. 1988; 34: 507-515PubMed Google Scholar, 9Pietarinen P. Raivio K. Devlin R.B. Crapo J.D. Chang L.Y. Kinnula V.L. Am. J. Respir. Cell Mol. Biol. 1995; 13: 434-441Crossref PubMed Scopus (54) Google Scholar). However, the mechanism to maintain high antioxidant activities in A-MΦ has not been understood because of its heterogeneity and lack of availability to study. Colony-stimulating factors (CSFs) such as granulocyte-macrophage CSF (GM-CSF) and macrophage-CSF (M-CSF) play important roles in survival and differentiation of monocytes/MΦ. Previously, we reported that CSFs such as GM-CSF and M-CSF stimulate MΦ generation from human monocytes, but GM-CSF-induced MΦ (GM-MΦ) and M-CSF-induced MΦ (M-MΦ), however, are distinct in their morphology, cell surface antigen expression (c-fms, CD14, CD71, and 710F), and sensitivity to human immunodeficiency virus, type I (HIV-I) infection (10Akagawa K.S. Nippon Saikingaku Zasshi. 1994; 49: 385-393Crossref PubMed Scopus (3) Google Scholar, 11Akagawa K. Hum. Cell. 1994; 7: 116-120PubMed Google Scholar, 12Matsuda S. Akagawa K. Honda M. Yokota Y. Takebe Y. Takemori T. AIDS Res. Hum. Retroviruses. 1995; 11: 1031-1038Crossref PubMed Scopus (67) Google Scholar, 13Akagawa K.S. Takasuka N. Nozaki Y. Komuro I. Azuma M. Ueda M. Naito M. Takahashi K. Blood. 1996; 88: 4029-4039Crossref PubMed Google Scholar, 14Akagawa K.S. Jpn. J. Med. Mycol. 1997; 38: 209-214Crossref Scopus (3) Google Scholar). Other studies also demonstrated that human monocyte-derived GM-MΦ and M-MΦ are distinct in their expression of CD14, integrin, and antibody-dependent cellular cytotoxicity activity (15Young A.D. Lowe D.L. Clark C.S. J. Immunol. 1990; 145: 607-615PubMed Google Scholar, 16De Nichilo M.O. Burns G.F. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 2517-2521Crossref PubMed Scopus (100) Google Scholar, 17De Nichilo M.O. Yamada K.M. J. Biol. Chem. 1996; 271: 11016-11022Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 18Keler T. Wallace P.K. Vitale L.A. Russoniello C. Sundarapandiyan K. Graziano R.F. Deo Y.M. J. Immunol. 2000; 164: 5746-5752Crossref PubMed Scopus (42) Google Scholar). Numerous studies show that the phenotype of human A-MΦ closely resembles that of GM-MΦ in morphology (fried egg-like shape) (19Nakata K. Akagawa K.S. Fukayama M. Hayashi Y. Kadokura M. Tokunaga T. J. Immunol. 1991; 147: 1266-1272PubMed Google Scholar), the expression of cell surface antigens (c-fmslow, CD14low, CD71+, and 710F+) (11Akagawa K. Hum. Cell. 1994; 7: 116-120PubMed Google Scholar, 13Akagawa K.S. Takasuka N. Nozaki Y. Komuro I. Azuma M. Ueda M. Naito M. Takahashi K. Blood. 1996; 88: 4029-4039Crossref PubMed Google Scholar,20Radzun H.J. Kreipe H. Heidorn K. Parwaresch M.R. J. Leukocyte Biol. 1988; 44: 198-204Crossref PubMed Scopus (13) Google Scholar, 21Andreesen R. Brugger W. Scheibenbogen C. Kreutz M. Leser H.G. Rehm A. Lohr G.W. J. Leukocyte Biol. 1990; 47: 490-497Crossref PubMed Scopus (183) Google Scholar, 22Hirata T. Bitterman P.B. Mornex J.F. Crystal R.G. J. Immunol. 1986; 136: 1339-1345PubMed Google Scholar), and function (resistance to MΦ-tropic HIV-I infection) (12Matsuda S. Akagawa K. Honda M. Yokota Y. Takebe Y. Takemori T. AIDS Res. Hum. Retroviruses. 1995; 11: 1031-1038Crossref PubMed Scopus (67) Google Scholar,23Nakata K. Weiden M. Harkin T. Ho D. Rom W.N. Mol. Med. 1995; 1: 744-757Crossref PubMed Google Scholar). In contrast, M-MΦ are elongated and spindle-shaped, express c-fmshigh and CD14high, which are similar to the phenotype of anaerobic peritoneal MΦ (11Akagawa K. Hum. Cell. 1994; 7: 116-120PubMed Google Scholar, 20Radzun H.J. Kreipe H. Heidorn K. Parwaresch M.R. J. Leukocyte Biol. 1988; 44: 198-204Crossref PubMed Scopus (13) Google Scholar, 21Andreesen R. Brugger W. Scheibenbogen C. Kreutz M. Leser H.G. Rehm A. Lohr G.W. J. Leukocyte Biol. 1990; 47: 490-497Crossref PubMed Scopus (183) Google Scholar, 24Hashimoto S. Yamada M. Motoyoshi K. Akagawa K.S. Blood. 1997; 89: 315-321Crossref PubMed Google Scholar), and are sensitive to MΦ-tropic HIV-I infection (12Matsuda S. Akagawa K. Honda M. Yokota Y. Takebe Y. Takemori T. AIDS Res. Hum. Retroviruses. 1995; 11: 1031-1038Crossref PubMed Scopus (67) Google Scholar). These findings suggest that CSF is one of the critical factors in the determination of phenotypical characteristics of tissue MΦ in the human system, and CSF-induced monocyte-derived MΦ are available to analyze tissue MΦ. In the present study, we investigated whether the antioxidant states of GM-MΦ are at similar levels to those of A-MΦ by assessment of H2O2 sensitivity and catalase activity. We found that GM-MΦ express high basal and inducible levels of catalase activity, are highly resistant to H2O2 compared with M-MΦ, and inhibit H2O2 production when stimulated with microbial stimulants. We also observed that catalase activity and sensitivity to H2O2 in GM-MΦ are at similar levels to those in A-MΦ. These findings suggest that GM-CSF but not M-CSF induces a strong antioxidant system in human tissue MΦ during the differentiation. RPMI 1640 medium (Nissui Seiyaku Co., Ltd., Tokyo, Japan) was supplemented with 3 mg/ml glutamine (Sigma), 100 units/ml penicillin G potassium (Banyu Seiyaku Co., Ltd., Tokyo, Japan), 100 μg/ml streptomycin (Meiji Seika Co., Ltd., Tokyo, Japan), 10% of autoclaved NaHCO3, and finally 10% heat-inactivated fetal calf serum (Z. L. Bockneck Laboratories Inc., Ontario, Canada). Fetal calf serum and distilled water were shown to contain 3 pg and less than 1 pg of lipopolysaccaride per ml by the Limullus amebocytelysate test, respectively. Recombinant human GM-CSF (1 × 108 units/mg) and recombinant human M-CSF (2 × 108 units/mg) were kindly provided by Schering-Plough Japan (Osaka, Japan) and Morinaga Milk Industry Co., Ltd. (Tokyo, Japan), respectively. Peripheral blood mononuclear cells were obtained from venous blood drawn from normal healthy volunteers as described previously (12Matsuda S. Akagawa K. Honda M. Yokota Y. Takebe Y. Takemori T. AIDS Res. Hum. Retroviruses. 1995; 11: 1031-1038Crossref PubMed Scopus (67) Google Scholar, 13Akagawa K.S. Takasuka N. Nozaki Y. Komuro I. Azuma M. Ueda M. Naito M. Takahashi K. Blood. 1996; 88: 4029-4039Crossref PubMed Google Scholar). Briefly, peripheral blood mononuclear cells were isolated by centrifugation on a Ficoll-Metrizoate density gradient (Lymphoprep; Nycomed, Oslo, Norway) and then placed into monocyte-isolating plates (MSP plates; Japan Immunoresearch Laboratories, Co., Ltd., Takasaki, Japan) for 2 h at 37 °C in a humidified 5% CO2 atmosphere (CO2 incubator). More than 97% of the recovered cells were judged to be monocytes based on morphology, nonspecific esterase staining (cells were stained using a kit for α-naphthyl butyrate esterase), CD14 positivity, and their ability to phagocytize latex particles. Monocytes (2.5 × 105 per ml or 5 × 105 per 2 ml in 12- or 6-well tissue culture plates, respectively) were then cultured with a optimal concentration of GM-CSF (500 units/ml) or M-CSF (104 units/ml) for 7 days at 37 °C in a CO2 incubator. During the culture, monocytes underwent morphologic changes characteristic of monocytes to MΦ differentiation such as an increase in their size and adherence. Human A-MΦ (2.5 × 105 per ml or 5 × 105 per 2 ml in 12- or 6-well tissue culture plates, respectively) were obtained from healthy volunteers (non-smokers without pathogenesis) by bronchoalveolar lavage (4Nakata K. Gotoh H. Watanabe J. Uetake T. Komuro I. Yuasa K. Watanabe S. Ieki R. Sakamaki H. Akiyama H. Kudoh S. Naitoh M. Satoh H. Shimada K. Blood. 1999; 93: 667-673Crossref PubMed Google Scholar, 25Goto H. Yuasa K. Sakamaki H. Nakata K. Komuro I. Iguchi M. Okamura T. Ieki R. Tanikawa S. Akiyama H. Onozawa Y. Mochida Y. Bone Marrow Transplant. 1996; 17: 855-860PubMed Google Scholar). All volunteers agreed with a document to permit the use of A-MΦ in part of this study, as informed consent. A-MΦ were incubated in plastic dishes for 1 h at 37 °C in a CO2 incubator, and non-adherent cells were removed by repeated washing. Cell viability was assessed by trypan blue dye exclusion. The number of adherent monocytes and monocyte-derived MΦs was determined by the method described previously by Nakagawara and Nathan (26Nakagawara A. Nathan C.F. J. Immunol. Methods. 1983; 56: 261-268Crossref PubMed Scopus (131) Google Scholar). Briefly, cultures were depleted of medium by gentle aspiration and then replenished with 1% (w/v) cetyltrimethyl ammonium bromide (Cetavlon; Wako Pure Chemical Industries, Ltd., Osaka, Japan) in 0.1 m citric acid with 0.05% (w/v) naphthol blue black (Sigma) at room temperature for 3 min. This treatment readily lysed the adherent cells and liberated stained intact nuclei, which were then counted using a TATAI hemocytometer (American Optical). Intracellular and extracellular catalase activity was measured according to the method described by Aebi (27Aebi H. Methods Enzymol. 1984; 105: 121-126Crossref PubMed Scopus (18933) Google Scholar). Briefly, MΦ were cultured in the phenol red-free medium (Life Technologies, Inc.) supplemented with the indicated concentrations of M-CSF or GM-CSF. Culture supernatants were harvested at 48 h for the measurement of extracellular catalase. To measure the intracellular catalase, cell lysates were prepared with a specific lysis buffer (10 mmol/liter EDTA, 2% Triton-X, 0.05% deoxycholic acid in phosphate-buffered saline, pH 7.4) and then with mmol/liter buffer 2 ml of the was into a by 1 ml of mmol/liter H2O2 in buffer activity was measured by the of H2O2 at in a Co., Japan) at The was into catalase activity based on the of human erythrocyte catalase 5 × number The activity is shown as per (2.5 × 105 or per of protein using a protein kit Laboratories, of and were as described previously K.S. Takasuka N. Nozaki Y. Komuro I. Azuma M. Ueda M. Naito M. Takahashi K. Blood. 1996; 88: 4029-4039Crossref PubMed Google Scholar). Briefly, cells were lysed with mmol/liter and 0.1 to a was by of 2 and by centrifugation at for at °C and then with and (10 was by with and and then to a on the under and in mmol/liter for 5 the was in buffer 3 Inc., and at °C for 3 for catalase or was in buffer a human catalase or as a All were using a system with were at 37 °C in and °C in in for and then using a Co., Ltd., Tokyo, Cell lysates were prepared with buffer mmol/liter 10% 100 mmol/liter and Cell lysates were by 10% and then to an using a system Tokyo, The was with Osaka, Japan) at °C to nonspecific and then incubated at °C with 1 μg/ml of and Inc., or normal in (10 mmol/liter pH mmol/liter supplemented with the was incubated at room temperature for 1 h with with supplemented with the specific were with on of H2O2 was by the reported by De and Nathan J. Nathan C.F. J. Immunol. Methods. PubMed Scopus Google Scholar). In cultured MΦ × per 100 in tissue culture were with phosphate-buffered saline, 100 of mmol/liter (Sigma), 1 mmol/liter 1 (Sigma) in buffer mmol/liter mmol/liter mmol/liter mmol/liter mmol/liter with mmol/liter was into the the of or heat-killed Staphylococcus the was placed in a Laboratories Inc., and was for at 37 H2O2 was from the of using the H2O2 × is the for the is the at is the in an and are the in the at and and is the amount of 3 to at the of the MΦ generated from human monocytes by CSF and and A-MΦ were cultured in the medium the indicated concentrations of H2O2 for 48 h and then cell viability was was a marked in their to H2O2 M-MΦ were with and 1 mmol/liter H2O2, 100 and of the cells of the cells were in 0.1 mmol/liter H2O2. In contrast, more than of GM-MΦ were when with mmol/liter H2O2. GM-MΦ were about 50-fold more resistant to H2O2 than A-MΦ also a strong to H2O2, and the level of was similar to that of GM-MΦ GM-MΦ and A-MΦ were more resistant to H2O2 than M-MΦ, we the levels of cell and extracellular catalase activity that H2O2 to in these catalase activity in the culture supernatants obtained from GM-MΦ incubated for 48 h was about than that from M-MΦ and in GM-MΦ and M-MΦ, respectively) 2 Culture supernatants obtained from A-MΦ also high extracellular catalase activity and the level was similar to that of GM-MΦ 2 In with the findings of the enzyme activity, protein levels of extracellular catalase in GM-MΦ and A-MΦ cultures were about than that in M-MΦ cultures by using 2 catalase activity in M-MΦ lysates at h was about 1 those in and were about 5 In with the enzyme activity, protein levels of catalase these MΦ lysates were catalase protein levels in GM-MΦ and A-MΦ lysates were than that in M-MΦ and the was about 3 the findings suggest that expression of catalase is M-MΦ and GM-MΦ or we the levels of catalase mRNA these MΦs at h their by mRNA in GM-MΦ was about than that in M-MΦ, which was similar to that in A-MΦ and protein levels of intracellular catalase and mRNA expression of the catalase in monocyte-derived MΦs and A-MΦ. activities and protein levels of catalase from MΦ lysates at h of were as indicated in the for not mRNA levels of catalase and were in (10 from these MΦs at 3 h of by is a in basal levels of catalase activity M-MΦ and GM-MΦ or the findings their distinct to the in catalase activity was the in sensitivity to H2O2 was about We whether the expression of catalase in monocyte-derived these MΦs were for 3 h with 0.1 mmol/liter H2O2, catalase mRNA in GM-MΦ was to about that in M-MΦ not we whether zymosan induces catalase in these MΦs were stimulated for 3 h with 0.1 mg/ml catalase mRNA in GM-MΦ, but not in M-MΦ, also about To that catalase protein was by induction of the catalase via or microbial we a of catalase protein in MΦ lysates The levels of catalase protein in lysates of GM-MΦ stimulated for h with H2O2 or zymosan to about such induction of catalase protein was not observed in lysates of M-MΦ or microbial catalase induction in both and protein levels was also observed in A-MΦ with H2O2 or and the induction level was similar to that in GM-MΦ These findings indicate that GM-MΦ and A-MΦ a marked ability to induce catalase expression in both and protein levels in response to H2O2 or microbial but M-MΦ this demonstrated GM-MΦ and A-MΦ but not M-MΦ express high levels of catalase activity. These findings suggest the that GM-MΦ, but not M-MΦ, has a marked ability to H2O2. shown in when GM-MΦ and A-MΦ were stimulated with 1 mg/ml zymosan for M-MΦ and GM-MΦ H2O2 and 0.1 H2O2, respectively. findings were obtained when these MΦs were stimulated with 1 mg/ml heat-killed S. M-MΦ H2O2 GM-MΦ 0.1 H2O2. Both MΦs not produce H2O2 without These findings suggest that M-MΦ a large amount of H2O2, GM-MΦ, their distinct of catalase We in the present that GM-MΦ and A-MΦ are highly resistant to H2O2 via the high basal level of catalase activity and a marked ability to express catalase in response to H2O2. mmol/liter H2O2, similar to levels found on in the D. R. M. H. D. Care Med. 1993; PubMed Scopus Google Scholar, K. I. J.C. N. 1999; 89: Google Scholar), not induce cell of GM-MΦ and A-MΦ. strong antioxidant mechanism of human A-MΦ by high catalase activity to be long in an and to In to GM-MΦ and M-MΦ are sensitive to exogenous H2O2 to about In with the to H2O2, express levels of basal catalase activity and lack the ability to induce catalase expression in response to H2O2. M-MΦ also a large amount of with GM-MΦ in response to microbial 24Hashimoto S. Yamada M. Motoyoshi K. Akagawa K.S. Blood. 1997; 89: 315-321Crossref PubMed Google Scholar). These findings suggest the that MΦ by M-CSF or activity. In with the present M-CSF activity of in the MΦ by H2O2 production J. Med. PubMed Scopus Google Scholar, Exp. Immunol. 1995; PubMed Scopus (38) Google Scholar). In the present study, GM-MΦ and but not M-MΦ, a marked ability to induce catalase expression by exposure of low levels of H2O2 and which can their against of the of the catalase in human cells and cells demonstrated that in response to in the K. K. H. Y. K. H. Mol. Cell. Biol. PubMed Scopus Google Scholar, P. Crystal R.G. J. 1994; 93: PubMed Google Scholar). These however, express low levels of catalase activity, and to catalase but induces of the protein to their survival P. Crystal R.G. Res. 1993; PubMed Scopus Google Scholar, C. A. C.S. Crystal R.G. J. 1993; PubMed Scopus Google Scholar, C. P. Crystal R.G. P. M. P. Hum. PubMed Scopus Google Scholar). The present is the to that MΦs such as A-MΦ and GM-MΦ a marked ability to induce catalase expression in response to The however, marked in catalase activity as one of the antioxidant GM-MΦ and M-MΦ to the generation of MΦ heterogeneity during the differentiation of monocytes under the influence of Previous studies demonstrated that morphology, the expression of cell surface and to HIV-I infection of GM-MΦ those of human A-MΦ (11Akagawa K. Hum. Cell. 1994; 7: 116-120PubMed Google Scholar, 12Matsuda S. Akagawa K. Honda M. Yokota Y. Takebe Y. Takemori T. AIDS Res. Hum. Retroviruses. 1995; 11: 1031-1038Crossref PubMed Scopus (67) Google Scholar, 14Akagawa K.S. Jpn. J. Med. Mycol. 1997; 38: 209-214Crossref Scopus (3) Google Scholar, K. Akagawa K.S. Fukayama M. Hayashi Y. Kadokura M. Tokunaga T. J. Immunol. 1991; 147: 1266-1272PubMed Google Scholar, 20Radzun H.J. Kreipe H. Heidorn K. Parwaresch M.R. J. Leukocyte Biol. 1988; 44: 198-204Crossref PubMed Scopus (13) Google Scholar, 21Andreesen R. Brugger W. Scheibenbogen C. Kreutz M. Leser H.G. Rehm A. Lohr G.W. J. Leukocyte Biol. 1990; 47: 490-497Crossref PubMed Scopus (183) Google Scholar, 22Hirata T. Bitterman P.B. Mornex J.F. Crystal R.G. J. Immunol. 1986; 136: 1339-1345PubMed Google Scholar, K. Weiden M. Harkin T. Ho D. Rom W.N. Mol. Med. 1995; 1: 744-757Crossref PubMed Google Scholar). In the present study, we also show that catalase activity and H2O2 sensitivity of GM-MΦ also those of human A-MΦ. important of GM-CSF in A-MΦ function was also reported in GM-CSF or GM-CSF D. D. J.A. D.W. J. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar, A.D. M. A. J.A. Science. 1994; PubMed Scopus Google Scholar, J.A. J.A. J. 1999; PubMed Scopus Google Scholar, R. R. U. Y. K. A. S. R. J. Exp. Med. 1996; PubMed Scopus Google Scholar, D. S. L. L. W. PubMed Scopus Google Scholar). These findings and those of the present suggest that GM-CSF a critical in the of ability via catalase activity in human A-MΦ. We demonstrated that GM-MΦ are resistant to H2O2 and a of H2O2 by and via high catalase activity. In contrast, produce and a large amount of H2O2 because of their low catalase activity. We previously reported that M-MΦ has a to produce GM-MΦ (12Matsuda S. Akagawa K. Honda M. Yokota Y. Takebe Y. Takemori T. AIDS Res. Hum. Retroviruses. 1995; 11: 1031-1038Crossref PubMed Scopus (67) Google Scholar). Numerous studies shown that H2O2, HIV-I via in the HIV-I long S. N. J. 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