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Salt-inducible kinase 3 deficiency exacerbates lipopolysaccharide-induced
endotoxin shock accompanied by increased levels of pro-inflammatory molecules in
mice
#MMPMID25619259
Sanosaka M
; Fujimoto M
; Ohkawara T
; Nagatake T
; Itoh Y
; Kagawa M
; Kumagai A
; Fuchino H
; Kunisawa J
; Naka T
; Takemori H
Immunology
2015[Jun]; 145
(2
): 268-78
PMID25619259
show ga
Macrophages play important roles in the innate immune system during infection and
systemic inflammation. When bacterial lipopolysaccharide (LPS) binds to Toll-like
receptor 4 on macrophages, several signalling cascades co-operatively up-regulate
gene expression of inflammatory molecules. The present study aimed to examine
whether salt-inducible kinase [SIK, a member of the AMP-activated protein kinase
(AMPK) family] could contribute to the regulation of immune signal not only in
cultured macrophages, but also in vivo. LPS up-regulated SIK3 expression in
murine RAW264.7 macrophages and exogenously over-expressed SIK3 negatively
regulated the expression of inflammatory molecules [interleukin-6 (IL-6), nitric
oxide (NO) and IL-12p40] in RAW264.7 macrophages. Conversely, these inflammatory
molecule levels were up-regulated in SIK3-deficient thioglycollate-elicited
peritoneal macrophages (TEPM), despite no impairment of the classical signalling
cascades. Forced expression of SIK3 in SIK3-deficient TEPM suppressed the levels
of the above-mentioned inflammatory molecules. LPS injection (10 mg/kg) led to
the death of all SIK3-knockout (KO) mice within 48 hr after treatment, whereas
only one mouse died in the SIK1-KO (n = 8), SIK2-KO (n = 9) and wild-type (n = 8
or 9) groups. In addition, SIK3-KO bone marrow transplantation increased LPS
sensitivity of the recipient wild-type mice, which was accompanied by an
increased level of circulating IL-6. These results suggest that SIK3 is a unique
negative regulator that suppresses inflammatory molecule gene expression in
LPS-stimulated macrophages.
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