Research Topics
Department of Animal Sciences
Ph.D. (1976) University of Illinois
Research Topics
Research Interests
We are studying the reciprocal systems of communication that have recently been discovered between the immune and central nervous systems. This crosstalk between the brain and the immune system is necessary for coordination of physiological and behavioral responses that occur during infectious, autoimmune, neurodegenerative and neoplastic diseases. Leukocytes, as well as glial cells in the brain, synthesize and secrete a wide variety of molecules known as cytokines. We have shown that some of the inflammatory cytokines, like interleukin-1 and tumor necrosis factor, serve as communication molecules between the immune and central nervous system by causing animals and humans to display clinical symptoms or sickness following infection. In contrast, anti-inflammatory cytokines in the brain, such as IL-10 and IGF-I conteract these biological events.
We have also established
that IGF-I promotes the survival of promyeloid cells as well as neurons, and it
potently increases the differentiation of promyloid cells as well. Factor
dependent cell progenitors (FDCP) are murine promyeloid cells that die upon
removal of growth factors such as IL-3. Both IGF-I and IL-4, the receptors for
which both tyrosine phosphorylate a 185 kDa docking molecule known as Insulin
Receptor Substrate-2 (IRS-2, formally known as IL-4 Phosphorylated
Substrate or 4PS), promote the survival of FDCP cells by a process that
requires the activation of PI 3-kinase. Both IGF-I and IL-4 promote cell
survival by inhibiting apoptosis and by promoting an increase in the amount of
intracellular Bcl-2 relative to Bax. Human HL-60 promyeloid cells express
abundant receptors for IGF-I. These cells differentiate into polymorphonuclear
neutrophils when incubated with vitamin A or into monocytes when exposed to
vitamin D3. However, in the absence of fetal bovine serum, these cells
differentiate poorly. Addition of IGF-I promotes the differentiation of these
cells into granulocytes by inhibiting apoptosis, and this process requires
activation of PI 3-kinase. New results with vitamin D3 also show that IGF-I
increases differentiation of HL-60 cells into monocytes by a PI
3-kinase-dependent mechanism, but in this case IGF-I acts by inhibiting
expression of the cyclin-dependent kinase inhibitor p27KIP1
increasing cyclin E and by hyperphosphorylating the retinoblastoma
tumor suppressor protein. Collectively, our data point to an important role for
classical hormones and cytokines in the survival and development of cells in
both the immune and central nervous systems.
Key Words Recombinant DNA,
DNA-Protein
Interactions, Protein-Protein Interaction, Cellular Immunology, Lymphokines/Growth Factors,
Active Sites and Receptors, Hormones, Animal Cell and/or Tissue Culture,
Pharmaceuticals, Neurobiology, Analytical Chemiluminescence, Fluorescence
Spectroscopy and/or Microscopy
Current Research Funding
NIH, Private Industry