The Research Of SOCS1 Negative Regulating Lipopolysaccharide Signalling Of Kupffer Cells

Endotoxin (ET), also called lipopolysaccharide (LPS), is an integralcell wall component of Gram-negative bacteria. LPS can provokemagnanimous pro-inflammation medium such as interleukin-1(IL-1), tumornecrosis factor-α (TNF-α) and interferon (IFN) et al released and lead tosystemic inflammatory response syndrome(SIRS), sepsis, especiallymultiple organ dysfunction syndrome(MODS) and death by activatedmicrophage. However, different clinical manifestations were observed in host afterinfected with Gram-negative bacteria, suggesting that host existeddifferential endotoxin tolerance. In other words, LPS can induce host orcells to produce endotoxin tolerance besides provoke inflammatoryresponse. Endotoxin tolerance is a none or lower response state of host orcells to a lethal dose of LPS rechallenge after initial pretreatment with asublethal dose of LPS. The mechanisms of endotoxin tolerance are toocomplicated, however, and the underlying mechanisms are largelyunknown. Recently study showed, not only Gram-negative bacteria but alsothe others inflammation materials such as recombinant fimbrillin (rFimA),lipoarabinomannan (LAM), soluble tuberculosis factor (STF) andmacrophage activating lipotides 2 (MALP-2) et al could induce endotoxintolerance. Some scholars called these phenomenons as crosstalk tolerance.So we can see the complexity of the mechanisms of endotoxin tolerance. The clinical treatment of sepsis is a nodus yet. One of the importantreasons is the clinical applications of antibiotics. It is well known thatantibiotics can kill bacterials, but at the same time urge magnanimous LPSreleased from bacterials at last lead to the biological toxicity action of LPSin vivo prolonged. Therefore, if we well know the mechanisms ofendotoxin tolerance sufficiently and induce host to produce endotoxintolerance properly, maybe provide some referenced theories in theprevention and treatment of sepsis which caused by Gram-negativebacteria. Recently, cytokine signal suppressor SOCS1(suppressor of cytokinesignaling-1) was found to be induced by LPS and CpG-DNA stimulation inmicrophages. SOCS1 also called SSI-1(STAT-induced STAT inhibitor-1)and JAB-1(JAK binding protein-1). SOCS-1 initial identified as anintracellular negative-feedback molecule that inhibits overactivation of theJAK-STAT-mediated signal cacade initiated by various stimuli, includingIFN –γ, IL-4, IL-6 et al. SOCS1 was induced by these cytokines and soonbinded to JAKs at last inhibited the following signal transduction. Starr etal found SOCS1-deficient(SOCS1 KO) mice shown lethal pathologicalalterations in various organs including fulminant hepatitis and die within 3weeks after birth, whereas double disruption of SOCS1 and IFN-γ gene canreduce these pathological alterations as well as early death inSOCS1-deficient mice. It suggested that SOCS1 is a key molecule forIFN-γ signaling in vivo. So we can infer SOCS1 play a key role in theformation of endotoxin tolerance. Currently, 8 members of SOCS familywere found, which named SOCS1-7 and CIS(cytokine-inducibleSH2-domain containing). Among of them the expression of SOCS1 isearlier, maybe related with the mechanisms of initial endotoxin tolerance.More clinical cases such as serious trauma, burning, infection, shock,surgery operation et al frequently lead to thick proliferation ofGram-negative bacteria in intestine and release of much LPS, adding to theincreased permeability of intestine wall, at last lead to the increasedabsorption of endotoxin by portal vein way, then result in intestinalendotoxemia(IETM) in differential degree. The shifting of endotoxincaused by IETM first insult liver for liver is a key detoxication organ inhost, so it is thus clear that the mechanisms of LPS in liver directly relatedto the response of host that responded to LPS. Therefore, it is veryimportant to clear the mechanism of host liver which responded to LPSreduced the impairment of multi-organs such as fulminant hepatitis et al. Kupffer cells is one of the MPS which residents in hepatic sinusoid. Itoccupy above 80% of all inherent mi...