The scaffold protein JLP plays a key role in regulating ultraviolet B‐induced apoptosis in mice

The ultraviolet B (UVB) component of sunlight can cause severe damage to skin cells and even induce skin cancer. Growing evidence indicates that the UVB‐induced signaling network is complex and involves diverse cellular processes. In this study, we investigated the role of c‐Jun NH₂‐terminal kinase‐associated leucine zipper protein (JLP), a scaffold protein for mitogen‐activated protein kinase (MAPK) signaling cascades, in UVB‐induced apoptosis. We found that UVB‐induced skin epidermal apoptosis was prevented in Jlp knockout (KO) as well as in keratinocyte‐specific Jlp KO mice. Analysis of the repair of UVB‐induced DNA damage over time showed no evidence for the involvement of JLP in this process. In contrast, UVB‐stimulated p38 MAPK activation in the skin was impaired in both Jlp KO and keratinocyte‐specific Jlp KO mice. Moreover, topical treatment of UVB‐irradiated mouse skin with a p38 inhibitor significantly suppressed the epidermal apoptosis in wild‐type mice, but not in Jlp KO mice. Our findings suggest that JLP in skin basal keratinocytes plays an important role in UVB‐induced apoptosis by modulating p38 MAPK signaling pathways. This is the first study to show a critical role for JLP in an in vivo response to environmental stimulation.     

Pemphigus antibody induced phosphorylation of keratinocyte proteins

The pemphigus family of autoimmune blistering diseases is characterized by an autoantibody response to desmosomal cadherins in epithelia. Autoantibodies against desmogleins, desmosome cell adhesion molecules, induce loss of cell-cell adhesion that is characterized clinically by blister formation. The mechanism by which these autoantibodies induce loss of cell-cell adhesion is under active investigation, but appears to involve a coordinated intracellular response including activation of intracellular signaling and phosphorylation of a number of proteins in the target keratinocyte. Activation of p38 mitogen activated protein kinase may have a critical role in the acantholytic mechanism as inhibitors of p38MAPK block the ability of pemphigus IgG to induce blistering in pemphigus animal models.     

Pemphigus antibody induced phosphorylation of keratinocyte proteins

The pemphigus family of autoimmune blistering diseases is characterized by an autoantibody response to desmosomal cadherins in epithelia. Autoantibodies against desmogleins, desmosome cell adhesion molecules, induce loss of cell–cell adhesion that is characterized clinically by blister formation. The mechanism by which these autoantibodies induce loss of cell–cell adhesion is under active investigation, but appears to involve a coordinated intracellular response including activation of intracellular signaling and phosphorylation of a number of proteins in the target keratinocyte. Activation of p38 mitogen activated protein kinase may have a critical role in the acantholytic mechanism as inhibitors of p38MAPK block the ability of pemphigus IgG to induce blistering in pemphigus animal models.     

The anti-inflammatory effect of alloferon on UVB-induced skin inflammation through the down-regulation of pro-inflammatory cytokines

UVB irradiation can induce biological changes in the skin, modulate immune responses and activate inflammatory reactions leading to skin damage. Alloferon, which is isolated from the blood of an experimentally infected insect, the blow fly Calliphora vicina, is known for its anti-viral and anti-tumor activities in mice model. However, the effect of alloferon against UVB irradiation and its specific mechanism are still unknown. In this study, we investigated the effect of alloferon on UVB-induced cutaneous inflammation in a human keratinocyte cell line, HaCaT. RPA and ELISA data showed that alloferon decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-6 and IL-18, both on the mRNA and protein level. Western blot analysis was done to determine if alloferon regulates the MAPK signaling pathway since the MAPK signaling pathway is activated by numerous inflammatory mediators and environmental stresses including UVB irradiation. Alloferon inhibited the activation of p38 mitogen-activated protein kinase (MAPK) induced by UVB irradiation. Furthermore, the topical application of alloferon on the UVB exposed skin of hairless mice showed that alloferon treatment significantly inhibited an increase in epithelial thickness in chronic UVB-irradiated mouse skin. These findings suggest that alloferon has significant anti-inflammatory effects not only on UVB-induced inflammation in the human keratinocyte cell line, HaCaT, but also on mouse skin.     

p38 mitogen-activated protein kinase (p38 MAPK)-mediated autoimmunity: Lessons to learn from ANCA vasculitis and pemphigus vulgaris

Evidence is beginning to accumulate that p38 mitogen activated protein kinase (p38 MAPK) signaling pathway plays an important role in the regulation of cellular and humoral autoimmune responses. The exact mechanisms and the degree by which the p38 MAPK pathway participates in the immune-mediated induction of diseases have started to emerge. This review discusses the recent advances in the molecular dissection of the p38 MAPK pathway and the findings generated by reports investigating its role in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and autoimmune hepatitis. Application of newly-developed protocols based on sensitive flow cytometric detection has proven to be a useful tool in the investigation of the phosphorylation of p38 MAPK within different peripheral blood mononuclear cell populations and may help us to better understand the enigmatic role of this signaling cascade in the induction of autoimmunity as well as its role in immunosuppressive-induced remission. Special attention is paid to reported data proposing a specific role for autoantibody-induced activation of p38 MAPK-mediated immunopathology in the pathogenesis of autoimmune blistering diseases and anti-neutrophilic antibody-mediated vasculitides.     

Interleukin 17A Promotes Pneumococcal Clearance by Recruiting Neutrophils and Inducing Apoptosis through a p38 Mitogen-Activated Protein Kinase-Dependent Mechanism in Acute Otitis Media

Streptococcus pneumoniae is a Gram-positive and human-restricted pathogen colonizing the nasopharynx with an absence of clinical symptoms as well as a major pathogen causing otitis media (OM), one of the most common childhood infections. Upon bacterial infection, neutrophils are rapidly activated and recruited to the infected site, acting as the frontline defender against emerging microbial pathogens via different ways. Evidence shows that interleukin 17A (IL-17A), a neutrophil-inducing factor, plays important roles in the immune responses in several diseases. However, its function in response to S. pneumoniae OM remains unclear. In this study, the function of IL-17A in response to S. pneumoniae OM was examined using an in vivo model. We developed a model of acute OM (AOM) in C57BL/6 mice and found that neutrophils were the dominant immune cells that infiltrated to the middle ear cavity (MEC) and contributed to bacterial clearance. Using IL-17A knockout (KO) mice, we found that IL-17A boosted neutrophil recruitment to the MEC and afterwards induced apoptosis, which was identified to be conducive to bacterial clearance. In addition, our observation suggested that the p38 mitogen-activated protein kinase (MAPK) signaling pathway was involved in the recruitment and apoptosis of neutrophils mediated by IL-17A. These data support the conclusion that IL-17A contributes to the host immune response against S. pneumoniae by promoting neutrophil recruitment and apoptosis through the p38 MAPK signaling pathway.     

P38丝裂原活化蛋白激酶信号转导通路在免疫性疾病中的研究进展

P38丝裂原活化蛋白激酶(P38 mitogen activated protein kinase,P38MAPK)信号转导通路在机体的免疫应答反应中发挥着重要作用,包括与类风湿性关节炎、原发性干燥综合征、寻常型天疱疮、炎症性肠病、系统性红斑狼疮、骨关节病、银屑病、自身免疫性脑脊髓炎等疾病密切相关.其不仅参与免疫性疾病炎性介质的调节,还参与其发生发展相关基因的调控,因此探讨P38MAPK信号转导通路在免疫性疾病中的作用可为免疫性疾病在临床中的治疗研究提供新的思路.     

Engagement of Toll-like receptor 2 enhances interleukin (IL)-17+ autoreactive T cell responses via p38 mitogen-activated protein kinase signalling in dendritic cells

Functional analysis of single Toll-like receptors (TLRs) in vivo is necessary to understand how they shape the ocular inflammation involved in uveitis. In this study we explored the role and mechanisms of TLR-2 agonists on the autoreactive T helper type 17 (Th17) response in experimental autoimmune uveitis (EAU). Treatment by peptidoglycan (PGN), a specific TLR-2 agonist, remarkably increased mRNA levels of Th17-lineage genes interleukin (IL)-17A, IL-21 and RAR-related orphan receptor (ROR)γt and promoted antigen-specific Th17 response in EAU mice. A mixture of PGN and interphotoreceptor retinoid-binding protein peptide (IRBP_161–180) could effectively induce EAU in the absence of complete Freund''s adjuvant (CFA). PGN treatment also enhanced the pathogenic activities of activated antigen-specific Th17 cells in vivo. PGN significantly increased the production of IL-1β, IL-6 and IL-23 of dendritic cells (DCs) and enhanced their ability to promote IL-17⁺ uveitogenic T cells. Enhanced immunostimulatory activities of PGN-DCs depend upon p38 activation. Inhibition of p38 mitogen-activated protein kinase (MAPK) activity dramatically decreased IL-17 gene expression and antigen-specific Th17 responses stimulated by PGN-DCs. Our findings suggest that PGN treatment dramatically promotes the IL-17⁺ uveitogenic T cell responses via enhancing the immunostimulatory activities of DCs. This effect may be mediated, at least in part, by activation of the p38 signalling pathway in DCs.     

Differential T helper cell response in tuberculous pleuritis

Purpose: This study was conducted to understand the in vivo and in vitro immune responses and to find whether there exists any difference in the systemic and localized immune responses in tuberculous pleuritis. Methods: The in vivo levels of IFN-γand IL-4 were compared in plasma (BL) and pleural fluid (PF) of 47 tuberculous (TB) and 31 nontuberculous pleuritis (Non-TB) patients. In vitro cytokine response to various mycobacterial antigens was studied in 19 TB patients by ELISA. Both ex vivo and in vitro cytokine responses were further ascertained by intracellular cytokine staining on purified CD4⁺ T cells from pleural fluid mononuclear cells (PFMC) of 10 TB patients. Results: The ex vivo results showed a significant increase in IFN-γlevels and higher IFN-γ⁺ T cells in PF. On the other hand, in vitro results showed simultaneous increase in both IFN-γand IL-4 levels in the supernatants of antigen stimulated PFMC. Similarly antigen specific increase was observed in both IFN-γ⁺ and IL-4⁺ T cells in all cultured conditions. However, the percentile increase was more in IL-4 secreting T cells, significant for PPD stimulation (P 0.05), indicating that in vitro cellular response was dominated by Th2 type. Conclusions: These results showed a differential T-helper response in TB pleuritis suggestive of predominant Th1 in vivo and mixed response (Th1 and Th2) under in vitro conditions.     

Sdc1 Overexpression Inhibits the p38 MAPK Pathway and Lessens Fibrotic Ventricular Remodeling in MI Rats

Expression of the proteoglycan syndecan-1 (Sdc1) is increased in rats with myocardial infarction (MI). This study investigated the effects of Sdc1 overexpression on ventricular remodeling and cardiac function in MI and explored the possible mechanism through in vivo transfection of rats with recombinant adenovirus-carrying rat Sdc1 cDNA. Sprague–Dawley rats (n?=?48) underwent intramyocardial injection in the marginal zone of the infarcted area immediately after ligation of the left anterior descending artery. The rats were divided into four groups according to the solution injected: MI Ad-GFP-Sdc1 transfection group, MI Ad-GFP control group, MI saline group, and sham operation group. Cardiac function and collagen expression of each group were examined, and the roles of inflammation, apoptosis, and p38 MAKP signal transduction pathway were investigated. Compared with the rats in the sham operation group, ventricular weight and collagen content increased in MI rats, and cardiac function declined. Substantial inflammatory cell infiltration was seen in the marginal zone of the infarction area, and a great number of myocardial cells were apoptotic. The p38 MAPK signaling pathway was clearly activated. Rats in the MI Ad-GFP-Sdc1 transfection group showed decreased ventricular weight, reduced collagen synthesis, and significant improvement of ventricular remodeling and cardiac function. Post-MI inflammatory cell infiltration and apoptosis was reduced, and the p38 MAPK signaling pathway was inhibited. Overexpression of Sdc1 can improve post-MI ventricular remodeling, and it is possible that the improvement is achieved through reducing apoptosis and suppressing inflammatory response and through the p38 MAPK signal transduction pathway.     

p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation

Dendritic cells (DC) play a role in the regulation of immune responses to haptens, which in turn impact DC maturation. Whether beryllium (Be) is able to induce DC maturation and if this occurs via the MAPK pathway is not known. Primary monocyte-derived DCs (moDCs) models were generated from Be non-exposed healthy volunteers as a non-sensitized cell model, while PBMCs from BeS (Be sensitized) and CBD (chronic beryllium disease) were used as disease models. The response of these cells to Be was evaluated. The expression of CD40 was increased significantly (p < 0.05) on HLA-DP Glu69+ moDCs after 100 μM BeSO₄-stimulation. BeSO₄ induced p38MAPK phosphorylation, while IκB-α was degraded in Be-stimulated moDCs. The p38 MAPK inhibitor SB203580 blocked Be-induced NF-κB activation in moDCs, suggesting that p38MAPK and NF-κB are dependently activated by BeSO₄. Furthermore, in BeS and CBD subjects, SB203580 downregulated Be-stimulated proliferation in a dose-dependent manner, and decreased Be-stimulated TNF-α and IFNγ cytokine production. Taken together, this study suggests that Be-induces non-sensitized Glu69+ DCs maturation, and that p38MAPK signaling is important in the Be-stimulated DCs activation as well as subsequent T cell proliferation and cytokine production in BeS and CBD. In total, the MAPK pathway may serve as a potential therapeutic target for human granulomatous lung diseases.     

Modulation of IL-37 expression by triptolide and triptonide in THP-1 cells

IL-37 is an anti-inflammatory cytokine that was only recently identified, and it is highly expressed in tissues from patients with inflammatory and autoimmune diseases. Inflammatory cytokines and inflammatory stimuli can induce the upregulation of IL-37. However, it has not been reported whether anti-inflammatory medications induce the expression of IL-37. In this work, we uncovered, for the first time, that two main bioactive components, triptolide and triptonide, from the herb Tripterygium wilfordii Hook f. (TwHF), which possess anti-inflammatory activity, upregulate the expression of IL-37, and this expression was suppressed by ERK1/2 and p38 MAPK inhibitors. Overall, our research demonstrated, for the first time, that anti-inflammatory active components (triptolide and triptonide) upregulated the expression of IL-37 most likely via activation of the ERK1/2 and p38 MAPK pathways.     

An involvement of SR-B1 mediated p38 MAPK signaling pathway in serum amyloid A-induced angiogenesis in rheumatoid arthritis

Serum amyloid A (SAA) has been reported high expression in autoimmune diseases, such as rheumatoid arthritis (RA). However, detailed molecular mechanisms induced by SAA in the pathogenesis of RA are still unclear. Herein, we focused on the role of SAA–SR-B1 mediated p38 MAPK signaling pathway in the process of RA angiogenesis. Our results showed that both SAA and SR-B1 predominantly localized to vascular endothelial cells, lining and sublining layers in RA synovium. In a series of in vitro experiments with human umbilical vein endothelial cells (HUVECs), SAA induced the endothelial cells (ECs) proliferation, migration and tube formation. However, blockage of SR-B1 and p38 MAPK inhibited SAA-induced cells proliferation, migration and tube formation. In conclusion, our data showed a possible molecular mechanism for SAA–SR-B1 induced angiogenesis events via p38 MAPK signaling pathway.     

Lactobacillus acidophilus Induces Cytokine and Chemokine Production via NF-��B and p38 Mitogen-Activated Protein Kinase Signaling Pathways in Intestinal Epithelial Cells

Intestinal epithelial cells can respond to certain bacteria by producing an array of cytokines and chemokines which are associated with host immune responses. Lactobacillus acidophilus NCFM is a characterized probiotic, originally isolated from human feces. This study aimed to test the ability of L. acidophilus NCFM to stimulate cytokine and chemokine production in intestinal epithelial cells and to elucidate the mechanisms involved in their upregulation. In experiments using intestinal epithelial cell lines and mouse models, we observed that L. acidophilus NCFM could rapidly but transiently upregulate a number of effector genes encoding cytokines and chemokines such as interleukin 1α (IL-1α), IL-1β, CCL2, and CCL20 and that cytokines showed lower expression levels with L. acidophilus NCFM treatment than chemokines. Moreover, L. acidophilus NCFM could activate a pathogen-associated molecular pattern receptor, Toll-like receptor 2 (TLR2), in intestinal epithelial cell lines. The phosphorylation of NF-κB p65 and p38 mitogen-activated protein kinase (MAPK) in intestinal epithelial cell lines was also enhanced by L. acidophilus NCFM. Furthermore, inhibitors of NF-κB (pyrrolidine dithiocarbamate [PDTC]) and p38 MAPK (SB203580) significantly reduced cytokine and chemokine production in the intestinal epithelial cell lines stimulated by L. acidophilus NCFM, suggesting that both NF-κB and p38 MAPK signaling pathways were important for the production of cytokines and chemokines induced by L. acidophilus NCFM.     

Effect of sevoflurane treatment on microglia activation,NF-kB and MAPK activities

Microglia activation has been implicated in neurodegenerative disease. Sevoflurane is fluorinated methyl isopropyl ether with anti-inflammatory activity. In this study, we evaluated the potential effects of sevoflurane on lipopolysaccharides (LPS)-induced microglia activation. We treated primary microglia cells with sevoflurane prior to LPS treatment and tested the microglia migration, the productions of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-6 and interleukin-8. We also explored the effects of sevoflurane on NF-κB and p38 MAPK activation. Finally, we examined the effect of sevoflurane on cytokines production in rat brain. Sevoflurane significantly reduced LPS-induced microglial migration. Sevoflurane significantly decreased the production of pro-inflammatory cytokines both in vitro and in vivo. Sevoflurane attenuated activations of NF-κB and MAPK signaling pathways. Sevoflurane treatment decreased microglia activation by suppressing NF-kB and MAPK signaling pathways.