Js. Marshall et al., INTERLEUKIN (IL)-10 INHIBITS LONG-TERM IL-6 PRODUCTION BUT NOT PREFORMED MEDIATOR RELEASE FROM RAT PERITONEAL MAST CELLS, The Journal of clinical investigation, 97(4), 1996, pp. 1122-1128
Mast cells have been implicated in a number of diseases involving chro
nic inflammation including asthma, rheumatoid arthritis, and inflammat
ory bowel diseases. They are a potent source of several cytokines, inc
luding IL-6 and TNF-alpha. Freshly isolated rat peritoneal mast cells
will produce IL-6 in response to anti-IgE, LPS, PGE(1), or PGE(2); how
ever, the mechanisms by which such cytokine production is regulated ar
e poorly understood. IL-10 is recognized as an important immunoregulat
ory cytokine with effects on T cell development and the production of
inflammatory cytokines. IL-10 has previously been described to enhance
mast cell development in the context of IL-3 and IL-4. In the current
study, we have examined the ability of IL-10 to modulate rat peritone
al mast cell IL-6 and TNF-alpha production in response to a variety of
stimuli. We have observed that recombinant murine IL-10 can inhibit t
he production of both IL-6 and TNF-alpha by mast cells without alterin
g the degree of histamine release in response to anti-IgE. Concentrati
ons of IL-10 as low as 0.2 ng/ml were sufficient to inhibit IL-6 produ
ction by LPS- or anti-IgE-activated cells significantly. IL-10 also in
hibited PGE(1)- and PGE(2)-induced IL-6 production. The relative poten
cy of IL-10 as an inhibitor of mast cell IL-6 production was highly de
pendent upon the stimulus used, with a 10-fold difference in the IC50
for LPS- or anti-IgE-activated cells (0.21 ng/ml) and cells activated
with a combination of LPS and PGE, (2.29 ng/ml). This suggests that pr
ostanoids may limit the ability of IL-10 to modulate mast cell IL-6 pr
oduction in the context of inflammation. These data have important imp
lications for the regulation of mast cell IL-6 in inflammatory disease
s involving prostanoid production and the effects of treatment with cy
clooxygenase inhibitors. Our results also demonstrate a dual role for
IL-10 on mast cells as a growth factor and inhibitor of cytokine produ
ction.