This proposal concerns interleukin-1 (IL-1) as a key mediator of host responses to microbial invasion, inflammation, immunological reaction and injury. IL-1 is one of the first and most prominent molecular synthesized following the onset of infection or injury. Many of IL-1's effects are involved with pathological processes, and the host has mechanisms by which synthesis, processing, transport and activities of IL-1 are regulated. This proposal studies these various mechanisms. The experiments are designed to explore IL-1 production from human blood monocytes. Up to 5% of the total polyadenylated RNA codes for IL-1-beta in monocytes after stimulation. Mechanisms control the translation of this RNA into IL-1 protein whereas other mechanisms seem to control processing of the primary translation product into biologically active IL-1. Transcription, translation and processing of IL-1 are different in blood monocytes than in cultured cells lines. Therefore, these experiments are focused on each of the steps of IL-1 production in circulating human blood cells in health, in disease and under the influence of various disease modifying substances. special methods will be employed that prevent the transcription of Il-1 in monocytes due to adherence to surfaces. Two newly developed radioimmunoassays for IL-1-beta and Il-1- alpha will be used in a large study to establish what constitutes """"""""normal"""""""" Il-1 production. Immunoprecipitation and immunofluorescence using specific, non-cross reacting antibodies will be used to detect the sizes and cellular localization of IL-1. The specific biological activities of Il-1 differ with the molecular size and hence studies on the structure-function relationship of IL-1 are proposed in order to identify a putative active site(s). The evaluation of synthetic peptides will be performed and correlated with naturally occurring fragments of monocyte Il-1. An animal model of hemodynamic shock using toxic shock syndrome toxin is to be used to evaluate the systemic effects of Il-1, its fragments and substances that inhibit its biological activities. Two clinical models will be used to study Il-1 production in human subjects: the effect of supplemental fish oil diet and hemodialysis. These studies complement the basic investigations on the molecular control of IL-1 production. Finally, these studies examine the production and activity of IL-1 in models of endogenous amplification and inhibition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI015614-12
Application #
3480844
Study Section
Pathology A Study Section (PTHA)
Project Start
1986-12-01
Project End
1992-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
12
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Coll-Miró, Marina; Francos-Quijorna, Isaac; Santos-Nogueira, Eva et al. (2016) Beneficial effects of IL-37 after spinal cord injury in mice. Proc Natl Acad Sci U S A 113:1411-6
Tzanetakou, Vassiliki; Kanni, Theodora; Giatrakou, Sophia et al. (2016) Safety and Efficacy of Anakinra in Severe Hidradenitis Suppurativa: A Randomized Clinical Trial. JAMA Dermatol 152:52-59
Dinarello, Charles A; Joosten, Leo A B (2016) Inflammation in rheumatology in 2015: New tools to tackle inflammatory arthritis. Nat Rev Rheumatol 12:78-80
Bai, Xiyuan; Dinarello, Charles A; Chan, Edward D (2015) The role of interleukin-32 against tuberculosis. Cytokine 76:585-587
Bai, Xiyuan; Kinney, William H; Su, Wen-Lin et al. (2015) Caspase-3-independent apoptotic pathways contribute to interleukin-32?-mediated control of Mycobacterium tuberculosis infection in THP-1 cells. BMC Microbiol 15:39
Høgh Kølbæk Kjær, Anne Sofie; Brinkmann, Christel Rothe; Dinarello, Charles A et al. (2015) The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients. AIDS 29:1195-200
Nold-Petry, Claudia A; Lo, Camden Y; Rudloff, Ina et al. (2015) IL-37 requires the receptors IL-18R? and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat Immunol 16:354-65
Abbate, Antonio; Van Tassell, Benjamin Wallace; Christopher, Sanah et al. (2015) Effects of Prolastin C (Plasma-Derived Alpha-1 Antitrypsin) on the acute inflammatory response in patients with ST-segment elevation myocardial infarction (from the VCU-alpha 1-RT pilot study). Am J Cardiol 115:8-12
Cohen, Idan; Idan, Cohen; Rider, Peleg et al. (2015) IL-1? is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. Sci Rep 5:14756
Michels, Meta; de Mast, Quirijn; Netea, Mihai G et al. (2015) Normal free interleukin-18 (IL-18) plasma levels in dengue virus infection and the need to measure both total IL-18 and IL-18 binding protein levels. Clin Vaccine Immunol 22:650-5

Showing the most recent 10 out of 527 publications