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Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
The functional properties of infiltrating macrophages (M
) must
be tightly regulated to facilitate appropriate responses to complex
conditions in an inflammatory focus. This study was designed to
ascertain whether uncommitted M that have been exposed to
combinations of cytokines with opposing functions develop properties
dictated by one cytokine or by cytokine mixtures. Uncommitted rat bone
marrow-derived M (BMDMs) were incubated with IFN-
, TNF-
,
TGF-ß, IL-4, IL-6, and IL-10 alone or sequentially in combinations.
After 48 h, function was assessed by nitric oxide (NO) generation,
uptake of apoptotic neutrophils, and ß-glucuronidase expression.
IFN- followed 4 h later by TNF-induced NO generation. The
pretreatment of BMDMs before IFN- priming with TNF, TGF-ß, and
IL-4 suppressed NO generation by 87%, 92%, and 85%, respectively;
IL-10 had no effect. The same cytokines administered at 4 h after
IFN priming had no effect on NO generation. The uptake of apoptotic
polymorphonuclear leukocytes was augmented by TNF (40% vs 29%
controls; p < 0.05) and decreased by IFN-,
IL-10, and IL-4. The TNF response was unaffected by subsequent
treatment with IFN-, IL-4, or IL-10. Similarly, the decreased
polymorphonuclear leukocyte uptake induced by IFN-, IL-4, or
IL-10 was unaffected by the subsequent addition of TNF.
ß-glucuronidase expression was increased by TGF-ß and decreased by
IFN-. These responses were not modified by cytokines with the
opposing function. Thus, the functional response of BMDMs to complex
mixtures of cytokines was determined by the first cytokine to which
they were exposed. Once activated, BMDMs become unresponsive to
alternative activating signals, a finding which has obvious
implications for M function in vivo.
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