Macrophages play critical roles not only in cell-mediated immune responses to microbial infection but also in diverse non-septic inflammatory reactions such as occur in cancer, osteoarthritis, vasculitis, encephalitis,and diabetes. The objective of this project is to determine the role of T cell cognate interactions in signaling activation of macrophage effector functions. The role of both antigen specific and antigen nonspecific interactions will be examined. The role of T cell derived noncognate signals, such as IFN-gamma and IL-10, in modulating the effects of the cognate signals will also be considered. Recent evidence suggests that a cascade of signals is required for the induction of macrophage effector activities, such as generation of reactive nitrogen intermediates. Separate signal pathways may be involved in the induction of synthesis of inflammatory cytokines such as IL-1 and TNF-alpha, in the activation of the cytokine secretory machinery, and in induction of receptors for these and other cytokines. Events in macrophage activation that will be examined include induction of early activation genes such as myc, fos, and KE, induction of cytokine production, and induction of nitric oxide generation. Induction of cytokine production will be assayed by DNA-RNA hybridization and by immunoprecipitation of extracellular and intracellular cytokine. This will allow an assessment of degree of cytokine gene transcription, translation, and posttranslational processing and secretion. Subsequent studies will focus on the signal transduction pathways involved in cognate and noncognate signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI034875-01
Application #
2070090
Study Section
Immunobiology Study Section (IMB)
Project Start
1994-01-01
Project End
1996-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
East Tennessee State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Johnson City
State
TN
Country
United States
Zip Code
37614
Mukhopadhyay, A; Suttles, J; Stout, R D et al. (2001) Genetic deletion of the tumor necrosis factor receptor p60 or p80 abrogates ligand-mediated activation of nuclear factor-kappa B and of mitogen-activated protein kinases in macrophages. J Biol Chem 276:31906-12
Hoellman, J R; Suttles, J; Stout, R D (2001) Panning T cells on vascular endothelial cell monolayers: a rapid method for enriching naive T cells. Immunobiology 203:769-77
Clemons-Miller, A R; Cox, G W; Suttles, J et al. (2000) LPS stimulation of TNF-receptor deficient macrophages: a differential role for TNF-alpha autocrine signaling in the induction of cytokine and nitric oxide production. Immunobiology 202:477-92
Suttles, J; Milhorn, D M; Miller, R W et al. (1999) CD40 signaling of monocyte inflammatory cytokine synthesis through an ERK1/2-dependent pathway. A target of interleukin (il)-4 and il-10 anti-inflammatory action. J Biol Chem 274:5835-42
Stout, R D; Suttles, J (1997) T cell signaling of macrophage function in inflammatory disease. Front Biosci 2:d197-206
Poe, J C; Wagner Jr, D H; Miller, R W et al. (1997) IL-4 and IL-10 modulation of CD40-mediated signaling of monocyte IL-1beta synthesis and rescue from apoptosis. J Immunol 159:846-52
Krishnaswamy, G; Lakshman, T; Miller, A R et al. (1997) Multifunctional cytokine expression by human mast cells: regulation by T cell membrane contact and glucocorticoids. J Interferon Cytokine Res 17:167-76
Suttles, J; Evans, M; Miller, R W et al. (1996) T cell rescue of monocytes from apoptosis: role of the CD40-CD40L interaction and requirement for CD40-mediated induction of protein tyrosine kinase activity. J Leukoc Biol 60:651-7
Miller, A R; Suttles, J; Stout, R D (1996) Cytokine priming reduces dependence on TNF-R2 for TNF-alpha-mediated induction of macrophage nitric oxide generation. J Interferon Cytokine Res 16:1055-63
Stout, R D; Suttles, J; Xu, J et al. (1996) Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice. J Immunol 156:8-11

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