Janus kinase 2 is involved in lipopolysaccharide-induced activation of macrophages

137

100

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently identified molecule involved in the amplification of inflammation. To determine the regulation of TREM-1, we studied TREM-1 expression and soluble TREM-1 plasma levels upon i.v. LPS challenge in healthy humans in vivo and in vitro. Granulocyte TREM-1 expression was high at baseline and immediately down-regulated upon LPS exposure along with an increase in soluble TREM-1. Monocytes displayed a gradual up-regulation of TREM-1 upon LPS in vivo and in vitro. In vitro studies extended these findings to highly purified lipoteichoic acid and Streptococcus pneumoniae. Nonbacterial TLR ligands such as polyinosine-polycytidylic acid and imidazoquinoline, as well as the TLR9 ligand CpG, did not impact TREM-1 expression. The LPS-induced alterations in TREM-1 surface expression were not a result of increased TNF-α or IL-10. Inhibitor studies disclosed a PI3K-dependent pathway in LPS-induced up-regulation of TREM-1 on monocytes, whereas MAPK played a limited role.

Section: Resultscontrasting

confidence: 71%

Cutting Edge: Expression Patterns of Surface and Soluble Triggering Receptor Expressed on Myeloid Cells-1 in Human Endotoxemia

Knapp¹,

Gibot²,

Vos³

et al. 2004

137

100

“…Because we observed a reduction in cytokine production in Ad vector-transduced RAW264.7 cells by the overexpression of SOCS1, we predicted that the JAK/STAT signal might be involved in Ad vector-activated immune signaling. The activation of JAK2 leads to the production of IL-6 in LPS stimulation which is impaired by the overexpression of SOCS1 (28,33). In this study, we found that the inhibition of JAK2 autophosphorylation by JAK2 inhibitor II results in a reduction in the Ad vector-mediated production of IL-6 and TNF-␣ (Fig.…”

Section: Discussionmentioning

confidence: 52%

“…Initially, we examined the induction of SOCS1 mRNA expression after the transduction of Ad vectors into immune cells. We selected a mouse macrophage-like cell line, RAW264.7, as a model of immune cells, because this cell line is commonly used in studies of innate immune responses to pathogens (28,33). We used the luciferase-expressing Ad vector containing the RGD peptide in the HI loop of the fiber knob (AdRGD-L2) (29) as well as the luciferase-expressing conventional Ad vector (Ad-L2) for in vitro analysis.…”

Section: Ad Vector-mediated Inflammatory Cytokine Production In Macromentioning

confidence: 99%

Adenoviral Expression of Suppressor of Cytokine Signaling-1 Reduces Adenovirus Vector-Induced Innate Immune Responses

Sakurai

Tashiro

Kono

et al. 2008

Adenovirus (Ad) vectors are among the most commonly used viral vectors in gene therapy clinical trials. However, the application of Ad vectors has been limited to local injection in many cases, because the systemic administration of Ad vectors triggers innate immune responses such as inflammatory cytokine production and tissue damage. To overcome this limitation, it will be necessary to develop safer Ad vectors less likely to induce the innate immune response. In the present study, we demonstrated that a suppressor of cytokine signaling-1 (SOCS1)-expressing Ad vector, Ad-SOCS1, reduces the innate immune response induced by Ad vectors. RAW264.7-SOCS1, a macrophage-like cell line that stably expresses SOCS1, was shown to produce lower levels of inflammatory cytokines after the transduction of Ad vectors. The systemic administration of Ad-SOCS1 into mice elicited the reduced production of inflammatory cytokines, as compared with that elicited by control Ad vectors, i.e., luciferase-expressing Ad vector, Ad-L2. Furthermore, the coadministration of Ad-L2 with Ad-SOCS1 attenuated inflammatory cytokine production and liver toxicity as compared with injection with Ad-L2 alone, and this was achieved without the suppression of luciferase production in various organs. The JAK/STAT pathway was involved in Ad vector-mediated cytokine production, which was impaired by the overexpression of SOCS1. These findings indicate that Ad-SOCS1 could be useful for reducing Ad vector-mediated innate immunity.

“…This suggests that JAK2 plays an important role in the specific production of LTC 4 . Importantly, TLR4 activation by LPS induces immediate phosphorylation of JAK2, which is blocked by an anti-TLR4 neutralizing Ab (47).…”

Section: Discussionmentioning

confidence: 99%

Human Lung Mast Cells Mediate Pneumococcal Cell Death in Response to Activation by Pneumolysin

Cruse

Fernandes

Salort

et al. 2010

Mast cells are emerging as contributors to innate immunity. Mouse mast cells have a pivotal role in protection against bacterial infection, and human cord blood-derived mast cells reduce bacterial viability in culture. The objectives of this study were to determine whether human lung mast cells (HLMCs) might be protective against pneumococcal lung infection through direct antimicrobial activity. Tissue-derived HLMCs and the human mast cell lines HMC-1 and LAD2 were cocultured with wild-type and mutant pneumococci, and viability and functional assays were performed. Mast cells were also stimulated with purified pneumolysin. HLMCs killed wild-type serotype-2 (D39) pneumococci in coculture but had no effect on an isogenic pneumolysin-deficient (PLN-A) pneumococcus. D39 wild-type, but not PLN-A pneumococci, induced the release of leukotriene C4 from human mast cells in a dose-dependent manner, which was not accompanied by histamine release. Stimulation of mast cells with sublytic concentrations of purified pneumolysin replicated this effect. Furthermore, pneumolysin induced the release of the cathelicidin LL-37 from HLMCs, purified LL-37 reduced pneumococcal viability, and neutralizing Ab to LL-37 attenuated mast cell-dependent pneumococcal killing. In addition, at high concentrations, all pneumococcal strains tested reduced HLMC viability through a combination of pneumolysin and H2O2-dependent mechanisms. HLMCs exhibit direct antimicrobial activity to pneumococci through their activation by pneumolysin. This antimicrobial activity is mediated, in part, by the release of LL-37 from HLMCs. This suggests that mast cells provide an early warning system and potentially limit pneumococcal dissemination early in the course of invasive pulmonary pneumococcal disease.