LPS-Induced Upregulation of SHIP Is Essential for Endotoxin Tolerance

Abstract

An initial exposure to lipopolysaccharide (LPS) induces a transient state of hyporesponsiveness to a subsequent challenge with LPS. The mechanism underlying this phenomenon, termed endotoxin tolerance, remains poorly understood despite a recent resurgence of interest in this area. We demonstrate herein that SHIP(-/-) bone marrow-derived macrophages (BMmphis) and mast cells (BMMCs) do not display endotoxin tolerance. Moreover, an initial LPS treatment of wild-type BMmphis or BMMCs increases the level of SHIP, but not SHIP2 or PTEN, and this increase is critical for the hyporesponsiveness to subsequent LPS stimulation. Interestingly, this increase in SHIP protein is mediated by the LPS-induced production of autocrine-acting TGFbeta and neutralizing antibodies to TGFbeta block LPS-induced endotoxin tolerance. In vivo studies with SHIP(+/+) and SHIP(-/-) mice confirm these in vitro findings and show a correlation between the duration of endotoxin tolerance and elevated SHIP levels.

Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K

“…67,68 Paradoxically, in a series of reports from another group, SHIP1 blocked Tnf and Il6 secretion upon TLR3 or TLR4 stimulation, but induced Il12 and expression of surface co-stimulatory molecules upon TLR stimulation, suggesting a more complex role for SHIP1 in downstream TLR signaling. [69][70][71][72] Consequently, SHIP1-deficient DCs were functionally incompetent for priming Th1 effector T cells. 69,70 These conflicting reports warrant further and more detailed investigation into the molecular mechanism of SHIP1-mediated control of the TLR pathway.…”

Distinct Macrophage Subpopulations Characterize Acute Infection and Chronic Inflammatory Lung Disease

“…SHIP-1 is a hematopoietic-specific 59 inositol phosphatase that represses the antiapoptotic and proinflammatory PI3K pathway (20,26), which is of particular importance in MFs. M2 AMF polarization was first identified in SHIP-1 2/2 mice that spontaneously developed lung disease (8), making SHIP-1 2/2 mice an invaluable model for examining MF-mediated mechanisms underlying chronic lung disease.…”

Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M

“…In addition to IRAK-M, many negative regulators of TLR signaling have been identified, including the TLR homolog RP105, Src homology 2-containing inositol-5′-phosphatase (SHIP), short form of MyD88, ST2, SIGIRR, Triad3A, A20, and SOCS-1 (44)(45)(46)(47)(48)(49)(50)(51)(52). Many of these molecules have been implicated in the development of endotoxin tolerance.…”