MYD88‐dependent and ‐independent activation of TREM‐1 via specific TLR ligands

Triggering receptor expressed on myeloid cells (TREM)‐1 plays an important role in myeloid cell‐activated inflammatory responses. Although TLR ligands such as LPS and lipoteichoic acid have been shown to upregulate TREM‐1 expression in macrophage and neutrophils, the role of specific TLR in inducing the expression of TREM‐1 remains unclear. In this study, we investigated whether the presence of TLR is necessary for the expression of TREM‐1. We show that BM‐derived macrophages from TLR4 and TLR2 KO mice failed to induce expression of TREM‐1 message and protein in response to their specific ligands. Interestingly, the expression of TREM‐1 in response to LPS is not altered in myeloid differentiation factor 88 (MyD88) KO macrophages, suggesting that downstream of TLR a MyD88‐independent pathway induces the expression of TREM‐1. Inhibiting toll/IL‐1R domain‐containing adaptor‐inducing IFN‐β (TRIF) expression by siRNA decreased TREM‐1 expression in response to LPS, suggesting that the expression of TREM‐1 in response to LPS was mediated by the TRIF signaling pathway. On the other hand, the expression of TREM‐1 in response to lipoteichoic acid is dependent on MyD88 expression. These data indicate that the expression of TREM‐1 in response to TLR ligands occurs secondary to downstream signaling events and that the presence of TLR is necessary for the expression of TREM‐1 in response to their specific ligands. However, the downstream signaling required for the expression of TREM‐1 is dependent on the stimulus and the surface receptor through which the signaling is initiated.     

Mechanism of interleukin‐1β‐induced proliferation in rat hepatic stellate cells from different levels of signal transduction

Hepatic stellate cells (HSCs) are the major producers of collagen in the liver. Their conversion from resting cells to proliferative, contractile, and activated cells is a critical step leading to liver fibrosis that is characterized by the deposition of excessive extracellular matrix. Interleukin‐1 (IL‐1) may play a role in maintaining HSC in a proliferative state that is responsible for hepatic fibrogenesis. The aim of this study was to study the roles of the IL‐1 type I receptor (IL‐1R1), c‐Jun N‐terminal kinase (JNK), and activation protein‐1 (AP‐1) in IL‐1β–mediated proliferation in rat HSCs. We showed that IL‐1β can upregulate proliferation in rat HSCs; however, inhibition of the JNK pathway could inhibit HSCs proliferation. Furthermore, IL‐1β activated IL‐1R1 expression, the JNK signaling pathway, and AP‐1 activity in a time‐dependent manner in rat HSCs. These data demonstrate that IL‐1β could promote the proliferation of rat HSCs and that the IL‐1R1, JNK, and AP‐1 pathways were involved in this process. In summary, IL‐1β‐induced proliferation is possibly mediated by the IL‐1R1, JNK, and AP‐1 pathways in rat HSCs. Therefore, drugs that block these pathways may inhibit the proliferation of HSCs and suppress liver fibrosis.     

Inflammatory stress of pancreatic beta cells drives release of extracellular heat‐shock protein 90α

A major obstacle in predicting and preventing the development of autoimmune type 1 diabetes (T1D) in at‐risk individuals is the lack of well‐established early biomarkers indicative of ongoing beta cell stress during the pre‐clinical phase of disease. Recently, serum levels of the α cytoplasmic isoform of heat‐shock protein 90 (hsp90) were shown to be elevated in individuals with new‐onset T1D. We therefore hypothesized that hsp90α could be released from beta cells in response to cellular stress and inflammation associated with the earliest stages of T1D. Here, human beta cell lines and cadaveric islets released hsp90α in response to stress induced by treatment with a combination of pro‐inflammatory cytokines including interleukin‐1β, tumour necrosis factor‐α and interferon‐γ. Mechanistically, hsp90α release was found to be driven by cytokine‐induced endoplasmic reticulum stress mediated by c‐Jun N‐terminal kinase (JNK), a pathway that can eventually lead to beta cell apoptosis. Cytokine‐induced beta cell hsp90α release and JNK activation were significantly reduced by pre‐treating cells with the endoplasmic reticulum stress‐mitigating chemical chaperone tauroursodeoxycholic acid. The hsp90α release by cells may therefore be a sensitive indicator of stress during inflammation and a useful tool in assessing therapeutic mitigation of cytokine‐induced cell damage linked to autoimmunity.     

Heme oxygenase‐1 inhibits basophil maturation and activation but promotes its apoptosis in T helper type 2‐mediated allergic airway inflammation

The anti‐inflammatory role of heme oxygenase‐1 (HO‐1) has been studied extensively in many disease models including asthma. Many cell types are anti‐inflammatory targets of HO‐1, such as dendritic cells and regulatory T cells. In contrast to previous reports that HO‐1 had limited effects on basophils, which participate in T helper type 2 immune responses and antigen‐induced allergic airway inflammation, we demonstrated in this study, for the first time, that the up‐regulation of HO‐1 significantly suppressed the maturation of mouse basophils, decreased the expression of CD40, CD80, MHC‐II and activation marker CD200R on basophils, blocked DQ‐ovalbumin uptake and promoted basophil apoptosis both in vitro and in vivo, leading to the inhibition of T helper type 2 polarization. These effects of HO‐1 were mimicked by exogenous carbon monoxide, which is one of the catalytic products of HO‐1. Furthermore, adoptive transfer of HO‐1‐modified basophils reduced ovalbumin‐induced allergic airway inflammation. The above effects of HO‐1 can be reversed by the HO‐1 inhibitor Sn‐protoporphyrin IX. Moreover, conditional depletion of basophils accompanying hemin treatment further attenuated airway inflammation compared with the hemin group, indicating that the protective role of HO‐1 may involve multiple immune cells. Collectively, our findings demonstrated that HO‐1 exerted its anti‐inflammatory function through suppression of basophil maturation and activation, but promotion of basophil apoptosis, providing a possible novel therapeutic target in allergic asthma.     

SKA1 over‐expression promotes centriole over‐duplication,centrosome amplification and prostate tumourigenesis

Although spindle‐ and kinetochore‐associated protein 1 (Ska1) has previously been identified as essential for proper chromosome segregation, it is unknown whether it plays a role in tumour development. Here, we report that Ska1 over‐expression promotes prostate tumourigenesis. Immunohistochemistry and quantitative RT–PCR analysis revealed that Ska1 was over‐expressed in human prostatic intra‐epithelial neoplasia (PIN), the most likely prostate cancer precursor, and adenocarcinomas. Up‐regulation of Ska1 protein was also found to be tumour‐specific in breast, lung and other common human cancers. Importantly, prostate‐specific up‐regulation of Ska1 in a transgenic mouse model resulted in spontaneous tumourigenesis. Furthermore, in addition to its abundance in spindle microtubules and the outer kinetochore interface during mitosis, Ska1 was enriched at centrosomes in cultured cells. Depletion of Ska1 caused a failure of centrosome duplication, whilst Ska1 over‐expression led to centrosome amplification in human prostate epithelial cells via the induction of centriole over‐duplication. These epithelial cells harbouring extra centrosomes switched from a non‐tumourigenic to a tumourigenic state in nude mice. Taken together, these data indicate that Ska1 over‐expression promotes tumourigenesis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd     

S100A9 promotes human lung fibroblast cells activation through receptor for advanced glycation end‐product‐mediated extracellular‐regulated kinase 1/2, mitogen‐activated protein‐kinase and nuclear factor‐κB‐dependent pathways

S100A9 belongs to the S100 family of calcium‐binding proteins and plays a key role in many inflammatory conditions. Recent studies have found that S100A9 was elevated significantly in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients, and might be a biomarker for fibrotic interstitial lung diseases. However, the exact function of S100A9 in pulmonary fibrosis needs further studies. We performed this study to investigate the effect of S100A9 on human embryo lung fibroblast (HLF) proliferation and production of cytokines and collagen, providing new insights into the possible mechanism. S100A9 promoted proliferation of fibroblasts and up‐regulated expression of both proinflammatory cytokines interleukin (IL)‐6, IL‐8, IL‐1β and collagen type III. S100A9 also induced HLF cells to produce α‐smooth muscle actin (α‐SMA) and receptor for advanced glycation end‐product (RAGE). In addition, S100A9 caused a significant increase in extracellular‐regulated kinase (ERK)1/2 mitogen‐activated protein kinase (MAPK) phosphorylation, while the status of p38 and c‐Jun N‐terminal kinase (JNK) phosphorylation remained unchanged. Treatment of cells with S100A9 also enhanced nuclear factor kappa B (NF‐κB) activation. RAGE blocking antibody pretreatment inhibited the S100A9‐induced cell proliferation, cytokine production and pathway phosphorylation. S100A9‐mediated cell activation was suppressed significantly by ERK1/2 MAPK inhibitor and NF‐κB inhibitor. In conclusion, S100A9 promoted HLF cell growth and induced cells to secret proinflammatory cytokines and collagen through RAGE signalling and activation of ERK1/2 MAPK and NF‐κB pathways.     

Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease

The p62/sequestosome-1 is a multifunctional protein containing several protein-protein interaction domains. Through these interactions p62 is involved in the regulation of cellular signaling and protein trafficking, aggregation and degradation. p62 protein can bind through its UBA motif to ubiquitinated proteins and control their aggregation and degradation via either autophagy or proteasomes. p62 protein has been reported to be seen in association with the intracellular inclusions in primary and secondary tauopathies, α-synucleinopathies and other neurodegenerative brain disorders displaying inclusions with misfolded proteins. In Alzheimer's disease (AD), p62 protein is associated with neurofibrillary tangles composed primarily of hyperphosphorylated tau protein and ubiquitin. Increasing evidence indicates that p62 has an important role in the degradation of tau protein. The lack of p62 protein expression provokes the tau pathology in mice. Recent studies have demonstrated that the p62 gene expression and cytoplasmic p62 protein levels are significantly reduced in the frontal cortex of AD patients. Decline in the level of p62 protein can disturb the signaling pathways of Nrf2, cyclic AMP and NF-κB and in that way increase oxidative stress and impair neuronal survival. We will review here the molecular and functional characteristics of p62 protein and outline its potential role in the regulation of Alzheimer's pathogenesis.