Blood, 1 October 2001, Vol. 98, No. 7, pp. 2101-2107
HEMATOPOIESIS
Interleukin-18 stimulates hematopoietic cytokine and growth
factor formation and augments circulating granulocytes in mice
Takeharu Ogura,
Haruyasu Ueda,
Katsushi Hosohara,
Risa Tsuji,
Yuki Nagata,
Shin-ichiro Kashiwamura, and
Haruki Okamura
From the Biochemistry II group, Research Department,
Sawai Pharmaceutical, Osaka, Japan; and the Laboratory of Host
Defenses, Institute for Advanced Medical Sciences and the Department of
Emergency and Disaster Medicine, Hyogo College of Medicine, Hyogo,
Japan.
Because interleukin-18 (IL-18) is similar to IL-1 and is known to
be involved in the hematopoietic progenitor cell growth, the effect of
IL-18 on circulating cell populations was examined. Repeated
administration of IL-18 induced significant amounts of neutrophilia in
mice. In parallel, high levels of interferon-
(IFN-), IL-6, and
granulocyte-macrophage colony-stimulating factor (GM-CSF) were detected
in the serum of these mice. Interestingly, the cytokine profiles as
well as the cell populations in circulation altered around 2 weeks
after the beginning of IL-18 administration. A weak but definite
eosinophilia was observed concurrently with the appearance of serum
IL-5. Consistent with these observations, IL-18 induced secretion of
IFN-, GM-CSF, and IL-6 from splenocytes in culture. IL-18 also
induced low levels of IL-5 in the splenocyte culture, which was
inhibited by IL-12. However, markedly high levels of IL-5 were secreted
into the culture medium when splenocytes from IFN--deficient mice
were stimulated by IL-18. CD4+ T cells strongly responded
to IL-18 to secrete IL-5 and GM-CSF. IL-18 stimulated secretion of IL-6
and expression of G-CSF mRNA in splenic adherent cells. Expression of
IL-18 receptors was detected in CD4+ T cells and splenic
adherent cells (macrophages). These results show that IL-18 stimulates
CD4+ T cells and macrophages to secrete IL-5, GM-CSF, IL-6,
and granulocyte-colony stimulating factor in the absence of IL-12,
which in turn induces hematopoietic cell proliferation causing
neutrophilia and eosinophilia in mice.
