The major thrust of our research during the last several years has been the detailed characterization of novel """"""""interferon"""""""" mRNA species induced by poly(I) poly (C) in diploid human fibroblasts: a 1.3 kb """"""""interferon-beta2"""""""" species and a 1.8 kb """"""""interferon-beta3"""""""" species. The cytokine, to which we originally applied the name """"""""interferon-beta2"""""""" and which is now called """"""""interleukin-6,"""""""" has emerged as a major systemic alarm signal produced in response to tissue injury. IL-6 phosphoglycoproteins (size range 23-30 kDa) in turn affect the function of a wide variety of different cell types. IL-6 elicits major changes in the biochemical, physiological and immunological status of the host (e.g. the """"""""acute phase"""""""" response.) We have developed a broad research program which has already provided key insights into the structure and function of human IL-6. We propose to continue this effort in the following areas: I. MOLECULAR BIOLOGY: The hallmark of IL-6 gene regulation is the induction of the gene in many different tissues by inflammation-association cytokines (IL-1), TNF, PDGF, other IFNs). We plan to conduct detailed investigations of the following: cis-acting regulatory DNA elements in the IL-6 promoter and trans-acting wild-type and mutant transcription factors involved in the regulation of this gene, particularly focusing on the 23-bp MRE identified by us; tissue-specificity of IL-6 induction and the molecular events that lead to constitutive vs. inducible expression of IL- 6. II. BIOCHEMISTRY: Different tissues secrete multiple forms of IL-6 which are post-translationally modified. We plan to characterize these modifications; characterize the biochemical nature of IL-6 in human body fluids (particularly the 45 kDa IL-6 complex) and carry out structure- activity studies of natural and recombinant IL-6 proteins. III. CELL BIOLOGY: IL-6 regulates expression of specific genes in several different target, cells. We propose to explore the effects of IL-6, alone and in combination with IL-1, TNF and IFN-gamma, on plasma protein secretion by hepatocytes, monocytes and fibroblasts; characterize the novel IL-6 """"""""receptor"""""""" mRNA species found in fibroblasts and investigate the inhibition of epithelial cell proliferation by IL-6. IV. PATHOPHYSIOLOGY: High IL-6 levels are found in plasma and body fluids in acute inflammatory disease states. We shall investigates the significance of altered IL-6 levels (systemic and local) in patients with acute and chronic infections, neoplasia and autoimmune diseases; and explore the association between IL-6 haplotypes and specific disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI016262-13
Application #
3126626
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1979-09-01
Project End
1995-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
13
Fiscal Year
1991
Total Cost
Indirect Cost
Name
New York Medical College
Department
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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Sehgal, P B (1996) Interleukin-6-type cytokines in vivo: regulated bioavailability. Proc Soc Exp Biol Med 213:238-47
Sehgal, P B; Wang, L; Rayanade, R et al. (1995) Interleukin-6-type cytokines. Ann N Y Acad Sci 762:1-14
May, L T; Patel, K; Garcia, D et al. (1994) Sustained high levels of circulating chaperoned interleukin-6 after active specific cancer immunotherapy. Blood 84:1887-95
Romero, R; Yoon, B H; Mazor, M et al. (1993) A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes. Am J Obstet Gynecol 169:839-51
Romero, R; Yoon, B H; Mazor, M et al. (1993) The diagnostic and prognostic value of amniotic fluid white blood cell count, glucose, interleukin-6, and gram stain in patients with preterm labor and intact membranes. Am J Obstet Gynecol 169:805-16
Margulies, L; Sehgal, P B (1993) Modulation of the human interleukin-6 promoter (IL-6) and transcription factor C/EBP beta (NF-IL6) activity by p53 species. J Biol Chem 268:15096-100
May, L T; Neta, R; Moldawer, L L et al. (1993) Antibodies chaperone circulating IL-6. Paradoxical effects of anti-IL-6 ""neutralizing"" antibodies in vivo. J Immunol 151:3225-36
May, L T; Viguet, H; Kenney, J S et al. (1992) High levels of ""complexed"" interleukin-6 in human blood. J Biol Chem 267:19698-704
May, L T; Sehgal, P B (1992) Phosphorylation of interleukin-6 at serine54: an early event in the secretory pathway in human fibroblasts. Biochem Biophys Res Commun 185:524-30

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