IL-36α and IL-36γ expressions in the differential diagnosis of palmoplantar psoriasis and palmoplantar eczema: A retrospective histopathologic and immunohistochemical study.

BACKGROUND: Diagnosing hyperkeratotic lesions on the palms and soles is often challenging for both clinicians and pathologists. Interleukin (IL)-36 cytokines play an important role in the pathogenesis of psoriasis. METHODS: We retrospectively re-evaluated hematoxylin-eosin-stained biopsy specimens of 30 patients with clinically diagnosed palmoplantar psoriasis (PP) and 30 patients with palmoplantar eczema (PE), and then performed IL-36α and IL-36γ immunohistochemistry. RESULTS: Among the histopathologic features, thinning of the rete ridges and vertical alternation of parakeratosis and orthokeratosis had the highest positive predictive value (PPV) in diagnosing PP (72.7% and 69.3%, respectively). Immunohistochemically, patients with PP predominantly showed diffuse or focal strong expression with IL-36α and IL-36γ staining in the upper layers of the epidermis (86.7% and 83.3%, respectively). The comparison of the mean IL-36α and IL-36γ expression scores significantly differed between PP and PE (P < .001). Among all histopathologic and immunohistochemical features, diffuse strong expression of IL-36α and IL-36γ staining had the highest PPVs in favor of a diagnosis of PP (75% and 76.7%, respectively). CONCLUSIONS: Our data suggest that IL-36α and IL-36γ immunohistochemistry can be used in the differential diagnosis of PP and PE.

Effects of Elemental Mercury Vapor Inhalation on Arterial Blood Gases, Lung Histology, and Interleukin-1 Expression in Pulmonary Tissues of Rats.

We investigated the effects of elemental mercury vapor inhalation on arterial blood gases (ABGs), lung histology, and interleukin-1 (IL-1) expression in pulmonary tissues in rats. A total of 42 Sprague Dawley rats were divided randomly into three groups. Rats in the first group were used as the control (CG). A short-term group (STG) and a long-term group (LTG) were exposed to 500 µg/m3 of mercury vapor 2 hrs/day for 21 days and 65 days, respectively. After exposure periods were completed, arterial blood samples were obtained, and ABGs were measured. Lung tissue sections were prepared for histology evaluation and immune-stained to detect IL-1 expression. There was a significant decrease in body weight in both STG (15%) and LTG (22%) compared with the CG. In the LTG, six out of 14 (43%) rats died, including two males and four females, while none of the rats in the STG died during the experiment. In both STG and LTG, a significant acid-base imbalance was characterized by a significant decrease in blood pH values and a significant increase in PCO2 values. Both PO2 and SpO2 blood values were significantly decreased in the STG and LTG, while no changes were observed in HCO3 values in all groups. Histological evaluation of lung tissues revealed severe lesions characterized by pulmonary emphysema and inflammatory cellular infiltrate. IL-1 expression in lung tissues was not significantly different between exposed rats and control subjects. These results indicate significant alterations in blood acid-base status characterized by severe respiratory acidosis with hypoxemia and no evidence of compensatory alkalosis in rats after exposure to short- and long-term elementary mercury vapor.

Manganese salts function as potent adjuvants.

Aluminum-containing adjuvants have been used for nearly 100 years to enhance immune responses in billions of doses of vaccines. To date, only a few adjuvants have been approved for use in humans, among which aluminum-containing adjuvants are the only ones widely used. However, the medical need for potent and safe adjuvants is currently continuously increasing, especially those triggering cellular immune responses for cytotoxic T lymphocyte activation, which are urgently needed for the development of efficient virus and cancer vaccines. Manganese is an essential micronutrient required for diverse biological activities, but its functions in immunity remain undefined. We previously reported that Mn2+ is important in the host defense against cytosolic dsDNA by facilitating cGAS-STING activation and that Mn2+ alone directly activates cGAS independent of dsDNA, leading to an unconventional catalytic synthesis of 2'3'-cGAMP. Herein, we found that Mn2+ strongly promoted immune responses by facilitating antigen uptake, presentation, and germinal center formation via both cGAS-STING and NLRP3 activation. Accordingly, a colloidal manganese salt (Mn jelly, MnJ) was formulated to act not only as an immune potentiator but also as a delivery system to stimulate humoral and cellular immune responses, inducing antibody production and CD4+/CD8+ T-cell proliferation and activation by either intramuscular or intranasal immunization. When administered intranasally, MnJ also worked as a mucosal adjuvant, inducing high levels of secretory IgA. MnJ showed good adjuvant effects for all tested antigens, including T cell-dependent and T cell-independent antigens, such as bacterial capsular polysaccharides, thus indicating that it is a promising adjuvant candidate.

IL-36 in chronic inflammation and fibrosis - bridging the gap?

IL-36 is a member of the IL-1 superfamily and consists of three agonists and one receptor antagonist (IL-36Ra). The three endogenous agonists, IL-36α, -ß, and -γ, act primarily as proinflammatory cytokines, and their signaling through the IL-36 receptor (IL-36R) promotes immune cell infiltration and secretion of inflammatory and chemotactic molecules. However, IL-36 signaling also fosters secretion of profibrotic soluble mediators, suggesting a role in fibrotic disorders. IL-36 isoforms and IL-36 have been implicated in inflammatory diseases including psoriasis, arthritis, inflammatory bowel diseases, and allergic rhinitis. Moreover, IL-36 has been connected to fibrotic disorders affecting the kidney, lung, and intestines. This review summarizes the expression, cellular source, and function of IL-36 in inflammation and fibrosis in various organs, and proposes that IL-36 modulation may prove valuable in preventing or treating inflammatory and fibrotic diseases and may reveal a mechanistic link between inflammation and fibrosis.

Involvement of the cytokine TWEAK in the pathogenesis of psoriasis vulgaris, pustular psoriasis, and erythrodermic psoriasis.

Psoriasis is a common chronic inflammatory dermatitis in which various cytokines play a detrimental role. The cytokine tumor necrosis factor-related weak inducer of apoptosis (TWEAK) is involved in the pathogenesis of multiple inflammatory disorders. However, the potential role of TWEAK in various subtypes of psoriasis has not been studied in depth. To investigate whether the levels of TWEAK are associated with clinical traits and the levels of some known psoriasis-related cytokines, such as interleukin (IL)-17A, IL-22, interferon (IFN)-γ, and IL-36γ, 20 patients with psoriasis vulgaris (PV), 8 patients with pustular psoriasis (PP), 8 patients with erythrodermic psoriasis (EP), and 20 healthy controls (HCs) were recruited into this study. The levels of serum cytokines were detected by commercial enzyme-linked immunosorbent assay kits. The average levels of TWEAK, IL-17A, IL-22, IFN-γ, and IL-36γ were significantly higher in the psoriasis groups than in the HC group. Furthermore, there was a statistically significant correlation between TWEAK and IL-17A/IFN-γ in PV and IL-36γ in EP, but there was no correlation between TWEAK and IL-22 in any subtype of psoriasis. This study suggests that TWEAK may have a role in the pathogenesis of PV, PP, and EP via synergy with IL-17A, IFN-γ, or IL-36γ, but not with IL-22.

Serial Systemic Injections of Endotoxin (LPS) Elicit Neuroprotective Spinal Cord Microglia through IL-1-Dependent Cross Talk with Endothelial Cells.

Microglia are dynamic immunosurveillance cells in the CNS. Whether microglia are protective or pathologic is context dependent; the outcome varies as a function of time relative to the stimulus, activation state of neighboring cells in the microenvironment or within progression of a particular disease. Although brain microglia can be "primed" using bacterial lipopolysaccharide (LPS)/endotoxin, it is unknown whether LPS delivered systemically can also induce neuroprotective microglia in the spinal cord. Here, we show that serial systemic injections of LPS (1 mg/kg, i.p., daily) for 4 consecutive days (LPSx4) consistently elicit a reactive spinal cord microglia response marked by dramatic morphologic changes, increased production of IL-1, and enhanced proliferation without triggering leukocyte recruitment or overt neuropathology. Following LPSx4, reactive microglia frequently contact spinal cord endothelial cells. Targeted ablation or selective expression of IL-1 and IL-1 receptor (IL-1R) in either microglia or endothelia reveal that IL-1-dependent signaling between these cells mediates microglia activation. Using a mouse model of ischemic spinal cord injury in male and female mice, we show that preoperative LPSx4 provides complete protection from ischemia-induced neuron loss and hindlimb paralysis. Neuroprotection is partly reversed by either pharmacological elimination of microglia or selective removal of IL-1R in microglia or endothelia. These data indicate that spinal cord microglia are amenable to therapeutic reprogramming via systemic manipulation and that this potential can be harnessed to protect the spinal cord from injury.SIGNIFICANCE STATEMENT Data in this report indicate that a neuroprotective spinal cord microglia response can be triggered by daily systemic injections of LPS over a period of 4 d (LPSx4). The LPSx4 regimen induces morphologic transformation and enhances proliferation of spinal cord microglia without causing neuropathology. Using advanced transgenic mouse technology, we show that IL-1-dependent microglia-endothelia cross talk is necessary for eliciting this spinal cord microglia phenotype and also for conferring optimal protection to spinal motor neurons from ischemic spinal cord injury (ISCI). Collectively, these novel data show that it is possible to consistently elicit spinal cord microglia via systemic delivery of inflammogens to achieve a therapeutically effective neuroprotective response against ISCI.

Anti-inflammatory activity of emu oil-based nanofibrous scaffold through downregulation of IL-1, IL-6, and TNF-α pro-inflammatory cytokines.

Background Inflammation is one of the most important responses of the body against infection or disease, and it protects tissues from injury; however, it causes redness, swelling, pain, fever and loss of function. The aim of this present study was to evaluate the anti-inflammatory activity of emu oil (Eu) formulated nanofibrous scaffold in HFFF2 fibroblast cells. Materials and methods Eu was formulated successfully in nanofibers through the electrospinning method. Besides, the morphological and structural properties of Eu nanofibres were evaluated using Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The MTT assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) was performed to evaluate the HFFF2 fibroblast cells' viability. Also, real-time polymerase chain reaction (PCR) was used to evaluate the anti-inflammatory signaling pathway in treated HFFF2 cells with Eu nanofiber. Results Our study showed that the Eu nanofiber increased the viability of fibroblast HFFF2 cells (p < 0.05). Also, the expression of interleukin1 (IL1), IL6 and tumor necrosis factor- alpha (TNF-α) pro-inflammatory cytokines genes were significantly decreased in treated HFFF2 cells with Eu nanofiber (p < 0.05). Conclusions In conclusion, Eu nanofiber scaffold potentially can reduce the inflammation process through downregulation of IL-1, IL-6 and TNF-α cytokines.

Additive Therapeutic Effects of Mesenchymal Stem Cells and IL-37 for Systemic Lupus Erythematosus.

BACKGROUND: Although mesenchymal stem cells (MSCs) might offer a promising strategy for treating SLE, their immunoregulatory plasticity makes their therapeutic effects unpredictable. Whether overexpressing IL-37, an IL-1 family member with immunosuppressive activity, might enhance the therapeutic effects of these cells for SLE is unknown. METHODS: We genetically modified MSCs to overexpress IL-37 and assessed their effects on immune suppression in vitro. We also evaluated the effects of such cells versus effects of various controls after transplanting them into MRL/lpr mice (model of SLE). RESULTS: Stem cell characteristics did not appear altered in MSCs overexpressing IL-37. These cells had enhanced immunosuppression in vitro in terms of inhibiting splenocyte proliferation, reducing proinflammatory factors (IL-1ß, TNF-α, IL-17, and IL-6), and suppressing autoantibodies (anti-dsDNA and anti-ANA). Compared with animals receiving control MSCs or IL-37 treatment alone, MRL/lpr mice transplanted with IL-37-overexpressing cells displayed improved survival and reduced signs of SLE (indicated by urine protein levels, spleen weight, and renal pathologic scores); they also had significantly lower expression of proinflammatory factors, lower total antibody levels in serum and urine, lower autoantibody production, and showed reduced T cell numbers in the serum and kidney. Expression of IL-37 by MSCs can maintain higher serum levels of IL-37, and MSCs had prolonged survival after transplantation, perhaps through IL-37 suppressing the inflammatory microenvironment. CONCLUSIONS: Mutually reinforcing interaction between MSCs and IL-37 appears to underlie their additive therapeutic effects. Genetic modification to overexpress IL-37 might offer a way to enhance the stability and effectiveness of MSCs in treating SLE.

IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis.

Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.

Early induction of C/EBPß expression as a potential marker of steroid responsive colitis.

The precise mechanism of hydrocortisone immune regulation in the management of colitis is poorly understood. Whilst not without limitations, its ability to suppress pathology and rapidly improve patient clinical outcome is key. We were interested in identifying early markers of therapeutic responsiveness in order to identify patients' refractory to therapy. Chronic Th1-driven colitis was induced in AKR/J mice using a parasite infection, Trichuris muris. 35 days post infection, mice were treated with low dose hydrocortisone (2 mg/kg/) i.p. on alternate days. Response to therapy was assessed at a systemic and tissue level day 45 post infection. Histopathology, gene and protein analysis was conducted to determine cytokine and transcriptional profiles. The colonic transcriptional profile in steroid treated mice showed significant upregulation of a small subset of T cell associated genes, in particular C/EBPß, CD4, IL7R and STAT5a. Despite no change in either transcription or protein production in downstream cytokines IFN γ, TNFα IL-17 and IL-10, hydrocortisone treatment significantly reduced colonic pathology and restored colonic length to naïve levels. As expected, steroid treatment of chronic gut inflammation generated significant immunosuppressive effects characterized by histological improvement. Low dose hydrocortisone induced significant upregulation of a subset of genes associated with T cell maintenance and regulation, including C/EBPß. These data suggest that enhanced expression of C/EBPß may be one of a subset of early markers demonstrating an immune regulatory response to hydrocortisone therapy, potentially by stabilization of Treg function. These observations contribute to our understanding of the immune landscape after steroid therapy, providing a potential markers of therapeutic responders and those refractory to hydrocortisone treatment.

Analysis of caecal mucosal inflammation and immune modulation during Anoplocephala perfoliata infection of horses.

Anoplocephala perfoliata is the commonest equine tapeworm, the adult parasites are attached in groups close to the ileocaecal valve causing marked inflammatory pathology. This work aimed to characterize the nature of the in vivo mucosal immune response to A perfoliata, and to investigate the role of A perfoliata excretory-secretory components in modulating in vitro immune responses. Real-time PCR detected elevation of IL13 and TGFß transcription in early-stage A perfoliata infection. In late-stage infection, IL-13, IL4 and Ifn transcripts were reduced while the regulatory cytokines, TGFß, IL10 and the transcription factor FOXP3 were increased in tissue close to the site of A perfoliata attachment; indicating downregulation of T-cell responses to A perfoliata. In vitro, A perfoliata excretory-secretory products induced apoptosis of the Jurkat T-cell line and premature cell death of ConA stimulated equine peripheral blood leucocytes. Analysis of cytokine transcription patterns in the leucocyte cultures showed a marked inhibition of IL-1 and IL-2 suggesting that a lack of T-cell growth factor transcription underlies the mechanism of the induced equine T-cell death. These preliminary findings suggest A perfoliata may have the ability to down-regulate host T-cell responses.

Dietary Toll-Like Receptor Stimulants Promote Hepatic Inflammation and Impair Reverse Cholesterol Transport in Mice via Macrophage-Dependent Interleukin-1 Production.

Background: The mechanisms connecting dietary intake of processed foods with systemic inflammatory markers and cardiovascular risk remain poorly defined. We sought to compare the abundance of pro-inflammatory stimulants of innate immune receptors in processed foods with those produced by the murine ileal and caecal microbiota, and to explore the impact of their ingestion on systemic inflammation and lipid metabolism in vivo. Methods and results: Calibrated receptor-dependent reporter assays revealed that many processed foods, particularly those based on minced meats, contain pro-inflammatory stimulants of Toll-like receptor (TLR)-2 and TLR4 at concentrations which greatly exceed those produced by the endogenous murine ileal microbiota. Chronic dietary supplementation with these stimulants, at concentrations relevant to those measured in the Western diet, promoted hepatic inflammation and reduced several markers of reverse cholesterol transport (RCT) in mice. Hepatocytes were found to be insensitive to TLR2- and TLR4-stimulants directly, but their secretion of functional cholesterol acceptors was impaired by interleukin (IL)-1ß released by TLR-responsive hepatic macrophages. Hepatic macrophage priming by high-fat diet enhanced the impairment of RCT by ingested endotoxin, and this was reversed by macrophage depletion via clodronate liposome treatment, or genetic deficiency in the IL-1 receptor. Conclusion: These findings reveal an unexpected mechanism connecting processed food consumption with cardiovascular risk factors, and introduce the food microbiota as a potential target for therapeutic regulation of lipid metabolism.

Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina.

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. The neovascular (wet) form of AMD can be treated with intravitreal injections of different anti-vascular endothelial growth factor (VEGF) agents. Placental growth factor (PGF) is another member of the VEGF family of cytokines with pro-angiogenic and pro-inflammatory effects. Here, we aimed to compare single and combined inhibition of VEGF-A and PGF in the laser-induced mouse model of choroidal neovascularization (CNV) with a focus on the effects on retinal mononuclear phagocytes. METHODS: CNV was induced in C57BL/6J mice using a YAG-Laser. Immediately after laser damage antibodies against VEGF-A (aVEGF), anti-PGF (aPGF), aVEGF combined with aPGF, aflibercept, or IgG control were injected intravitreally in both eyes. Three and 7 days after laser damage, the vascular leakage was determined by fluorescence angiography. Lectin staining of retinal and RPE/choroidal flat mounts was used to monitor CNV. In situ mRNA co-expression of Iba1, VEGF and PGF were quantified using in situ hybridization. Retinal and RPE/choroidal protein levels of VEGF and PGF as well as the pro-inflammatory cytokines IL-6, IL1-beta, and TNF were determined by ELISA. RESULTS: Early (day 3) and intermediate (day 7) vascular leakage and CNV were significantly inhibited by PGF and VEGF-A co-inhibition, most effectively with the trap molecule aflibercept. While VEGF-A blockage alone had no effects, trapping PGF especially with aflibercept prevented the accumulation of reactive microglia and macrophages in laser lesions. The lesion-related mRNA expression and secretion of VEGF-A and PGF by mononuclear phagocytes were potently suppressed by PGF and partially by VEGF-A inhibition. Protein levels of IL-6 and IL1-beta were strongly reduced in all treatment groups. CONCLUSIONS: Retinal inhibition of PGF in combination with VEGF-A prevents vascular leakage and CNV possibly via modulating their own expression in mononuclear phagocytes. PGF-related, optimized strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of wet AMD patients.

Pancreatic Stellate Cells Serve as a Brake Mechanism on Pancreatic Acinar Cell Calcium Signaling Modulated by Methionine Sulfoxide Reductase Expression.

Although methionine sulfoxide reductase (Msr) is known to modulate the activity of multiple functional proteins, the roles of Msr in pancreatic stellate cell physiology have not been reported. In the present work we investigated expression and function of Msr in freshly isolated and cultured rat pancreatic stellate cells. Msr expression was determined by RT-PCR, Western blot and immunocytochemistry. Msr over-expression was achieved by transfection with adenovirus vectors. Pancreatic stellate cells were co-cultured with pancreatic acinar cells AR4-2J in monolayer culture. Pancreatic stellate and acinar cell function was monitored by Fura-2 calcium imaging. Rat pancreatic stellate cells were found to express MsrA, B1, B2, their expressions diminished in culture. Over-expressions of MsrA, B1 or B2 were found to enhance ATP-stimulated calcium increase but decreased reactive oxygen species generation and lipopolysaccharide-elicited IL-1 production. Pancreatic stellate cell-co-culture with AR4-2J blunted cholecystokinin- and acetylcholine-stimulated calcium increases in AR4-2J, depending on acinar/stellate cell ratio, this inhibition was reversed by MsrA, B1 over-expression in stellate cells or by Met supplementation in the co-culture medium. These data suggest that Msr play important roles in pancreatic stellate cell function and the stellate cells may serve as a brake mechanism on pancreatic acinar cell calcium signaling modulated by stellate cell Msr expression.

Umbilical Cord Blood Mesenchymal Stem Cells Enhance Lipopolysaccharide-Induced IL-10 and IL-37 Production in THP-1 Cells.

Umbilical cord blood mesenchymal stem cells (UCB-MSCs) have been shown to be a source of stem cells for use in cellular therapies and have immunomodulatory effects on several immune cells in an inflammatory environment. However, whether UCB-MSCs have immunomodulatory effects against lipopolysaccharide (LPS)-induced inflammatory cytokine secretion in macrophages and whether it is involved in phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway remain unclear. After co-culture of UCB-MSCs and phorbol 12-myristate 13-acetate (PMA)-activated human THP-1 cells using a transwell system, it showed that LPS significantly induced increases in the expression levels of interleukin 10 (IL-10), interleukin 37 (IL-37), phospho-PI3K (p-PI3K), and phospho-Akt (p-Akt) in macrophages. UCB-MSCs upregulated the expression of IL-10, IL-37, p-PI3K, and p-Akt, while it had no obvious effect on PI3K and Akt levels. Inhibitors of PI3K (LY294002) significantly suppressed the expression of IL-10, IL-37, p-PI3K, and p-Akt; however, it had no effect on the expression levels of PI3K and Akt. The present study demonstrated that UCB-MSCs increased the LPS-stimulated expression of IL-10 and IL-37 in macrophages through the PI3K/Akt signaling pathway.

Culprit Drugs Induce Specific IL-36 Overexpression in Acute Generalized Exanthematous Pustulosis.

Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remain incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis. Here, we show that IL-36 cytokines, in particular IL-36γ, are highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36γ. Such an IL-36γ overexpression was not observed in patients with drug-induced maculopapular rash. In vitro, the causative drug specifically induced IL-36γ release either directly by the patient's peripheral blood monocytes or indirectly by keratinocytes in the presence of autologous peripheral blood mononuclear cells. Such culprit drug induction of IL-36γ secretion in vitro was specific for AGEP and involved toll-like receptor 4 sensing the drug/albumin complex as a danger signal. Our results suggest that IL-36γ secretion by monocytes/macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP.

Bv8-Like Toxin from the Frog Venom of Amolops jingdongensis Promotes Wound Healing via the Interleukin-1 Signaling Pathway.

Prokineticins are highly conserved small peptides family expressed in all vertebrates, which contain a wide spectrum of functions. In this study, a prokineticin homolog (Bv8-AJ) isolated from the venom of frog Amolops jingdongensis was fully characterized. Bv8-AJ accelerated full-thickness wounds healing of mice model by promoting the initiation and the termination of inflammatory phase. Moreover, Bv8-AJ exerted strong proliferative effect on fibroblasts and keratinocytes isolated from newborn mice by activating interleukin (IL)-1 production. Our findings indicate that Bv8 is a potent wound healing regulator and may reveal the mechanism of rapid wound-healing in amphibian skins.

Ischemic Preconditioning Preserves Liver Energy Charge and Function on Hepatic Ischemia/Reperfusion Injury in Rats.

BACKGROUND: Cell energy during ischemia/reperfusion depends on mechanisms including adenosine diphosphate degradation, oxygen species and cytokine liberation, neutrophil infiltration, and endothelial dysfunction. Preconditioning-a brief ischemic episode that confers a state of protection against subsequent ischemia-reperfusion injury-involves NO and adenosine production, reduction in oxygen species liberation, and preservation of microcirculation. During hypoxia, constitutive NO production assures adequate oxygen delivery and reduced energy loss. The aim was to determine the role of ischemic preconditioning in the stimulation of constitutive endothelial nitric oxide (NO) production and its effect on energy charge, radical oxygen species generation, cytokine liberation, and neutrophil infiltration during reperfusion. MATERIALS AND METHODS: Rats were assigned to one of four groups depending on the preconditioning protocol: hepatic ischemia/reperfusion, or hepatic ischemia/reperfusion and ischemic preconditioning, for 5, 10, or 20 min. A portosystemic shunt was established between the portal and left jugular veins during ischemia. RESULTS: Preconditioning produced rises in plasma nitrites, but no rise in inducible nitric oxide synthase gene expression. A 5 or 10 min preconditioning period allowed for higher energy charge, bile production, and glutathione levels, with less lipoperoxide, alanine aminotransferase, tumor necrosis factor-α, and interleukin-1 production and neutrophil infiltration, compared with 20 min or control. Survival was 80% in the G10 group, 70 in G5, 10 in GC, and 0% in the G20 group. CONCLUSIONS: Ten-min liver preconditioning improves survival and prevents energy loss during hepatic ischemia/reperfusion by stimulating constitutive NO production, maintaining glutathione concentrations and reducing oxygen species and proinflammatory cytokine generation as well as neutrophil infiltration.

The Role of Calcium in Inflammation-Associated Bone Resorption.

The aim of this mini-review is to discuss the role of calcium in the process of cytokine-mediated bone resorption in an effort to understand the role circulating calcium may play in the resorption of bone. The liberation of calcium and possibly phosphorus and magnesium by bone resorption may sustain and intensify the inflammatory response. We used a burn injury setting in humans and a burn injury model in animals in order to examine the effects on the bone of the systemic inflammatory response and identified the parathyroid calcium-sensing receptor as the mediator of increasing bone resorption, hence higher interleukin (IL)-1 production, and decreasing bone resorption, hence the lowering of circulating ionized calcium concentration. Thus, extracellular calcium, by means of the parathyroid calcium-sensing receptor, is able to modulate inflammation-mediated resorption.