IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor
Y. Hyodo et al., IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor, J IMMUNOL, 162(3), 1999, pp. 1662-1668
IL-18 is a powerful inducer of IFN-gamma production, particularly in collab
oration with IL-12, IL-18, like IL-12, also augments NK activity. Here we i
nvestigated the molecular mechanism underlying the up-regulation of killing
activity of NK cells by IL-18, IL-18, like IL-12, dose dependently enhance
d NK activity of splenocytes. This action was further enhanced by costimula
tion with IL-12. Treatment with anti-IL-2R Ab did not affect IL-18- and/or
IL-12-augmented NK activity, and splenocytes from IFN-gamma-deficient mice
showed enhanced NK activity. following stimulation with IL-12 and/or IL-18.
Splenocytes from the mice deficient in both IL-12 and IL-18 normally respo
nded to IL-18 and/or IL-12 with facilitated NK activity, suggesting that fu
nctional NK cells develop in the absence of IL-12 and IL-18. IL-18R, as wel
l as IL-12R mRNA, was constitutively expressed in splenocytes from SCID mic
e, which lack T cells and B cells but have intact NK cells, and in those fr
om IL-12 and IL-18 double knockout mice. NK cells isolated from SCID spleno
cytes expressed IL-18R on their surface. IL-18, in contrast to IL-12, did n
ot enhance mRNA expression of perforin, a key molecule for exocytosis-media
ted cytotoxicity. However, pretreatment with concanamycin A completely inhi
bited this IL-18- and/or IL-12-augmented NK activity. Furthermore, IL-18, l
ike IL-12, failed to enhance NK activity of splenocytes from perforin-defic
ient mice. These data suggested that NK cells develop and express IL-12R an
d IL-18R in the absence of IL-12 or IL-18, and that both IL-18 and IL-12 di
rectly and independently augment perforin-mediated cytotoxic activity of NK
cells.