The Hirsh lab

The Inflammation Page

Interleukin-1 (IL-1) is a proinflammatory cytokine with multiple pleiotropic actions. Interleukin-1 receptor antagonist (IL-1ra) functions as an anti-inflammatory cytokine in downregulating inflammatory and innate immune responses. It antagonizes IL-1 by competing for the IL-1 receptor but does not activate signal transduction. We have generated transgenic mice that overproduce IL-1ra. These mice are more resistant to a proinflammatory challenge with endotoxin than are wildtype mice but are more susceptible to a pathogenic bacterial infection. We have also generated IL-1ra gene knockout mice. Conversely, they are more sensitive to a proinflammatory challenge and more resistant to a bacterial infection. Thus, IL-1ra helps maintain a critically balanced level of IL-1 activity - excess IL-1 leads to vascular leakage, shock and ultimately death; too little IL-1 activity diminishes the ability of the animal to thwart an infection. We find that after challenge, excess IL-1ra in transgenics alters the levels of other cytokines, reduces leukocytosis, and diminishes MHC presentation. We are interested in understanding the molecular, genetic and cellular bases of these responses to inflammation and infection. We are deciphering these physiological pathways by measuring changes in various cytokine levels and following leukopoeisis.
We have also discovered a role for IL-1ra in the maintenance of homeostasis, as our knockout mice are runted and sickly even in the absence of stimuli. Certain aspects of the phenotype are strain dependent. Therefore, the IL-1ra knockout mouse is a "sensitized strain". We are interested in using the knockout mice to identify new disease modifying genes that themselves may be causative in various pathogenic states.
Literature:

Josephs, M.D., Solorzano, C.C., Ksontini, R., Taylor, M., Topping, D., Abouhamze, A., Mackay, S.L.D., Hirsch, E., Hirsh, D., LaBow, M. and Moldawer, L.L. (2000). Modulation of the acute phase response to a turpentine abscess by altered expression of the IL-1 p80 receptor or IL-1 receptor antagonist. Am. J. Physiol. 278: R824-R830.
Irikura, V.M., Hirsch, E. and Hirsh, D. (1999). Effects of Interleukin-1 receptor antagonist overexpression on infection by Listeria momocytogenes. Infect Immun. 67, 1901-1903.
Ma, Y., Thornton, S. Boivin, G.P. Hirsh, D., Hirsch, R., and Hirsch, E. (1998). Altered susceptibility to collagen-induced arthritis in transgenic mice with aberrant expression of interleukin-1 receptor antagonist. Arthritis Rheum. 41, 1798-1805.
Hirsch, E., Irikura, V., Paul, S.M. and Hirsh, D. (1996). Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc. Natl. Acad. Sci. USA 93, 11008-11013.

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