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B
into Human Macrophages: Lipopolysaccharide-Induced, But Not Zymosan-Induced, Proinflammatory Cytokines Are Inhibited, But IL-10 Is Nuclear Factor-B Independent1
Kennedy Institute of Rheumatology, Hammersmith, London, United Kingdom
Macrophages are the major cytokine producers in chronic
inflammatory diseases, but the biochemical pathways regulating cytokine
production are poorly understood. This is because genetic tools to
dissect signaling pathways cannot be used in macrophages because of
difficulties in transfection. We have developed an adenoviral technique
to achieve high efficiency gene delivery into macrophages and recently
showed that spontaneous TNF-
production in rheumatoid
arthritis joint cells, chiefly from macrophages, is 75% blocked
by adenoviral transfer of I
B. In this report we use the same
adenovirus to investigate whether the production of a number of
proinflammatory cytokines (e.g., TNF-, IL-1ß, IL-6, and IL-8) from
human macrophages depends on NF-B. While the cytokine response to
certain inducers, such as LPS, PMA, and UV light, is blocked by
overexpression of IB, the response to zymosan is not. In
contrast, anti-inflammatory mediators (IL-10 and IL-1 receptor
antagonist) induced by LPS are only marginally inhibited by IB
excess. These studies demonstrate several new points about macrophage
cytokine production. First, there is heterogeneity of mechanisms
regulating both the proinflammatory and anti-inflammatory cytokines
within populations of a single cell type. In addition, the results
confirm the utility of the adenoviral technique for functional analysis
of cytokine induction. The results also confirm that there are
autocrine and paracrine interactions regulating cytokine synthesis
within a single cell type. The selectivity of NF-B blockade for
proinflammatory but not anti-inflammatory mediators indicates that
in macrophages, NF-B may be a good target for the treatment of
chronic inflammatory diseases.
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R. Rezzonico, V. Imbert, R. Chicheportiche, and J.-M. Dayer Ligation of CD11b and CD11c {beta}2 integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1{alpha} (MIP-1{alpha}) and MIP-1{beta} production in primary human monocytes through a pathway dependent on nuclear factor-{kappa}B Blood, May 15, 2001; 97(10): 2932 - 2940. [Abstract] [Full Text] [PDF]
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M. D. Wheeler, S. Yamashina, M. Froh, I. Rusyn, and R. G. Thurman Adenoviral gene delivery can inactivate Kupffer cells: role of oxidants in NF-{kappa}B activation and cytokine production J. Leukoc. Biol., April 1, 2001; 69(4): 622 - 630. [Abstract] [Full Text]
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 W. C. Russell Update on adenovirus and its vectors J. Gen. Virol., November 1, 2000; 81(11): 2573 - 2604. [Full Text]
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B. M J Foxwell, J. Bondeson, F. Brennan, and M. Feldmann Adenoviral transgene delivery provides an approach to identifying important molecular processes in inflammation: evidence for heterogenecity in the requirement for NFkappa B in tumour necrosis factor production Ann Rheum Dis, November 1, 2000; 59(90001): i54 - 59. [Abstract] [Full Text] [PDF]
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J. S. Koh, Z. Wang, and J. S. Levine Cytokine Dysregulation Induced by Apoptotic Cells Is a Shared Characteristic of Murine Lupus J. Immunol., October 15, 2000; 165(8): 4190 - 4201. [Abstract] [Full Text] [PDF]
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A. K. De, K. M. Kodys, B. S. Yeh, and C. Miller-Graziano Exaggerated Human Monocyte IL-10 Concomitant to Minimal TNF-{alpha} Induction by Heat-Shock Protein 27 (Hsp27) Suggests Hsp27 Is Primarily an Antiinflammatory Stimulus J. Immunol., October 1, 2000; 165(7): 3951 - 3958. [Abstract] [Full Text] [PDF]
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E. M. Benkhart, M. Siedlar, A. Wedel, T. Werner, and H. W. L. Ziegler-Heitbrock Role of Stat3 in Lipopolysaccharide-Induced IL-10 Gene Expression J. Immunol., August 1, 2000; 165(3): 1612 - 1617. [Abstract] [Full Text] [PDF]
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J. G. Vallejo, P. Knuefermann, D. L. Mann, and N. Sivasubramanian Group B Streptococcus Induces TNF-{alpha} Gene Expression and Activation of the Transcription Factors NF-{kappa}B and Activator Protein-1 in Human Cord Blood Monocytes J. Immunol., July 1, 2000; 165(1): 419 - 425. [Abstract] [Full Text] [PDF]
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H. D. Brightbill, S. E. Plevy, R. L. Modlin, and S. T. Smale A Prominent Role for Sp1 During Lipopolysaccharide- Mediated Induction of the IL-10 Promoter in Macrophages J. Immunol., February 15, 2000; 164(4): 1940 - 1951. [Abstract] [Full Text] [PDF]
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 L. L. Reznikov, B. D. Shames, H. A. Barton, C. H. Selzman, G. Fantuzzi, S.-H. Kim, S. M. Johnson, and C. A. Dinarello Interleukin-1beta deficiency results in reduced NF-kappa B levels in pregnant mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2000; 278(1): R263 - R270. [Abstract] [Full Text] [PDF]
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S. Takashiba, T. E. Van Dyke, S. Amar, Y. Murayama, A. W. Soskolne, and L. Shapira Differentiation of Monocytes to Macrophages Primes Cells for Lipopolysaccharide Stimulation via Accumulation of Cytoplasmic Nuclear Factor kappa B Infect. Immun., November 1, 1999; 67(11): 5573 - 5578. [Abstract] [Full Text] [PDF]
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J. Bondeson, B. Foxwell, F. Brennan, and M. Feldmann Defining therapeutic targets by using adenovirus: Blocking NF-kappa B inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators PNAS, May 11, 1999; 96(10): 5668 - 5673. [Abstract] [Full Text] [PDF]
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W. Ma, W. Lim, K. Gee, S. Aucoin, D. Nandan, M. Kozlowski, F. Diaz-Mitoma, and A. Kumar The p38 Mitogen-activated Kinase Pathway Regulates the Human Interleukin-10 Promoter via the Activation of Sp1 Transcription Factor in Lipopolysaccharide-stimulated Human Macrophages J. Biol. Chem., April 20, 2001; 276(17): 13664 - 13674. [Abstract] [Full Text] [PDF]
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S.-H. Young, J. Ye, D. G. Frazer, X. Shi, and V. Castranova Molecular Mechanism of Tumor Necrosis Factor-alpha Production in 1right-arrow3-beta -Glucan (Zymosan)-activated Macrophages J. Biol. Chem., June 1, 2001; 276(23): 20781 - 20787. [Abstract] [Full Text] [PDF]
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