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Interleukin-1 receptor antagonist blocks chemokine production in the mixed
lymphocyte reaction
NW Lukacs, SL Kunkel, MD Burdick, PM Lincoln and RM Strieter
Department of Pathology, University of Michigan Medical School, Ann Arbor
48109-0602.
The mixed lymphocyte reaction (MLR) has previously been used to elucidate
pathways of cytokine activation and T-lymphocyte proliferation and is
regarded as a model that simulates responses in allograft rejection.
Studies have indicated that interleukin-1 (IL-1), a potent inflammatory
cytokine, may have an important activating role in the MLR response. The
discovery of a naturally occurring IL-1 receptor antagonist protein (IRAP)
has renewed interest in control of IL-1--dependent responses both in vitro
and in vivo. MLR cultures were used to study the role of IL-1 and IRAP in
the regulation of subsequent cytokines during a T-lymphocyte-mediated
alloantigen response. The temporal expression of IL-1 and IRAP during 5-day
one-way MLR assays suggested antagonistic production of the two cytokines.
IL-1 was produced early in the response, peaking at 4 hours through day 2,
subsequently declining to near-background levels on day 5 of culture. In
contrast, production of IRAP was delayed until day 2, steadily increased on
days 3 and 4, and peaked on day 5 of culture, which correlated with the
declining levels of IL-1. The addition of graded doses of IRAP (25 to 1,000
ng/mL) to MLR cultures decreased IL-1 production but had no effect on
T-lymphocyte proliferative response. In addition, IRAP had little effect on
the production of either IL-2 or tumor necrosis factor. The addition of 25
ng/mL of IRAP to MLR assays showed significantly decreased levels of two
potent chemotactic cytokines, IL-8 and macrophage inflammatory protein-1
alpha (MIP-1 alpha), at peak chemokine production on day 5 of culture. The
levels of IL-8 and MIP-1 alpha could be restored by the addition of IL-1 to
the IRAP-treated cultures. IL-8 and MIP-1 alpha represent the two different
families of chemotactic cytokines, C-X-C (IL-8) and C-C (MIP-1 alpha), and
potentially play important roles in the recruitment of leukocytes to a site
of immune allogeneic response. These studies indicate that regulation of
IL-1 by IRAP does not significantly reduce T-lymphocyte activation but can
regulate the production of chemokines involved in leukocyte recruitment.
Volume 82,
Issue 12,
pp. 3668-3674,
12/15/1993
Copyright © 1993 by The American Society of Hematology
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