scholarly journals Zhuanggu Guanjie herbal formula mitigates osteoarthritis via NF-κB transduction mechanism in vitro

2021 ◽  
Author(s):  
Guowei Gong ◽  
Yuzhong Zheng ◽  
Xuan Zhou ◽  
Zhi Dai ◽  
Juanhui Duan ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Raw Materials ◽  
Dependent Manner ◽  
Herbal Formula ◽  
Working Mechanism ◽  
Differentiated Cells ◽  
Osteoarthritis Treatment ◽  
Specific Proteins ◽  
Oxide Synthase

Abstract BackgroundZhuanggu Guanjie herbal formula, a famous Chinese prescription, which is commonly applied for mitigating bone-related problems, clinically. According to the China Pharmacopeia (CP, 2020), this herbal formula includes 12 raw materials, and the major components are Rehmanniae Radix (RR) and Psoraleae Fructus (PF). The anti-osteoarthritis properties of this herbal prescription are well-documented in CP (2020). However, the working mechanism of this ancient herbal formula has not been elucidated. Therefore, we would like to probe the anti-osteoarthritis pharmaceutical values of this ancient herbal prescription.Materials and methodsThe differentiated ATDC5 cells were employed in the following experiments. In the present study, the involvements of cytokine levels and hallmark proteins reflecting inflammatory responses in Zhuanggu Guanjie Capsule (ZGC)-induced differentiated cells were detected by RT-PCR, flow cytometer, western blot and laser confocal assays.ResultsThe cytokines and inflammation-specific proteins, i.e. interleukin (IL)-6, tumor necrosis factor- (TNF-) and inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostaglandin synthesis E2 (PGES-2) were robustly declined after incubating with ZGC for 48 hours, and the attenuation levels were in a dose-dependent manner. Furthermore, ZGC could also block NF-B translocation from cytosol to nucleus and which has been verified by the laser confocal microscope.ConclusionsThe in vitro studies have clarified the anti-osteoarthritis properties of ZGC and the working mechanism involved, and this herbal formula shed light on osteoarthritis treatment.

scholarly journals Electrospun Polydioxanone Loaded With Chloroquine Modulates Template-Induced NET Release and Inflammatory Responses From Human Neutrophils

2021 ◽  
Vol 9 ◽  
Author(s):  
Allison E. Fetz ◽  
Shannon E. Wallace ◽  
Gary L. Bowlin
Keyword(s):  
Growth Factor ◽  
Inflammatory Responses ◽  
Human Peripheral Blood ◽  
Early Time ◽  
Human Neutrophils ◽  
Late Time ◽  
Dependent Manner ◽  
Blood Neutrophils ◽  
Net Release

The implantation of a biomaterial quickly initiates a tissue repair program initially characterized by a neutrophil influx. During the acute inflammatory response, neutrophils release neutrophil extracellular traps (NETs) and secrete soluble signals to modulate the tissue environment. In this work, we evaluated chloroquine diphosphate, an antimalarial with immunomodulatory and antithrombotic effects, as an electrospun biomaterial additive to regulate neutrophil-mediated inflammation. Electrospinning of polydioxanone was optimized for rapid chloroquine elution within 1 h, and acute neutrophil-biomaterial interactions were evaluated in vitro with fresh human peripheral blood neutrophils at 3 and 6 h before quantifying the release of NETs and secretion of inflammatory and regenerative factors. Our results indicate that chloroquine suppresses NET release in a biomaterial surface area–dependent manner at the early time point, whereas it modulates signal secretion at both early and late time points. More specifically, chloroquine elution down-regulates interleukin 8 (IL-8) and matrix metalloproteinase nine secretion while up-regulating hepatocyte growth factor, vascular endothelial growth factor A, and IL-22 secretion, suggesting a potential shift toward a resolving neutrophil phenotype. Our novel repurposing of chloroquine as a biomaterial additive may therefore have synergistic, immunomodulatory effects that are advantageous for biomaterial-guided in situ tissue regeneration applications.

Pentoxifylline inhibits FMLP-induced macromolecular leakage

1995 ◽  
Vol 269 (1) ◽  
pp. H239-H245
Author(s):  
K. Nakagawa ◽  
F. N. Miller ◽  
A. W. Knott ◽  
M. J. Edwards
Keyword(s):  
Inflammatory Responses ◽  
Fluorescein Isothiocyanate ◽  
Histamine Receptor ◽  
Intracellular Camp ◽  
Dependent Manner ◽  
Cyclic Monophosphate ◽  
Endogenous Histamine ◽  
Camp Analogue

The acute inflammatory responses to the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) and the effects of pentoxifylline (PTXF) on the responses in vivo were studied. We used intravital microscopy with rat cremaster muscle preparation to determine inflammatory responses of microcirculation. Macromolecular leakage from postcapillary venules was evaluated by quantifying the extravasation of fluorescein isothiocyanate conjugated to bovine serum albumin. FMLP induced a rapid increase in macromolecular leakage, an increase in leukocyte-endothelium adhesion, and a decrease in blood flow in the microcirculation. PTXF inhibited FMLP-induced responses in a dose-dependent manner but failed to block the histamine-dependent leakage induced by compound 48/80. In addition, diphenhydramine, a histamine-receptor blocker, did not affect the macromolecular leakage induced by FMLP. The cell-permeable adenosine 3',5'-cyclic monophosphate (cAMP) analogue N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate mimicked PTXF's effects on the microcirculation and also inhibited FMLP-induced macromolecular leakage. PTXF is known to inhibit phosphodiesterase and increase intracellular cAMP, which modulates functions of endothelial cells, smooth muscle cells, and neutrophils in vitro. Our findings suggest that FMLP induces acute inflammatory responses through activation of neutrophils, independent of endogenous histamine release, and that PTXF inhibits these responses through elevated intracellular cAMP.

scholarly journals Modulatory effect of antibiotics on cytokine production by human monocytes in vitro.

1996 ◽  
Vol 40 (6) ◽  
pp. 1366-1370 ◽  
Author(s):  
K Morikawa ◽  
H Watabe ◽  
M Araake ◽  
S Morikawa
Keyword(s):  
Antimicrobial Agents ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Immunomodulatory Activity ◽  
Lymphocyte Function ◽  
Dependent Manner ◽  
Human Monocytes ◽  
Concentration Dependent Manner ◽  
Cytokine Synthesis

Some antimicrobial agents have been reported to modify the host immune and inflammatory responses both in vivo and in vitro. Fosfomycin (FOM) and clarithromycin (CAM) have immunomodulatory activity on human lymphocyte function. In the present study, we examined the effects of FOM and CAM on cytokine synthesis by lipopolysaccharide (LPS)-stimulated human monocytes in comparison with that of dexamethasone in vitro. The three drugs demonstrated positive or negative effects on the synthesis of various cytokines by LPS-primed monocytes. They suppressed the synthesis of tumor necrosis factor alpha, interleukin 1 alpha (IL-1 alpha), IL-1 beta, the IL-1 receptor antagonist, and granulocyte-macrophage colony-stimulating factor in a concentration-dependent manner at concentrations between 1.6 and 40 micrograms/ml. On the contrary, the drugs showed different actions on the synthesis of IL-6 and IL-10. Namely, FOM enhanced both IL-6 and IL-10 synthesis, CAM enhanced only IL-10 synthesis, but dexamethasone deeply suppressed the synthesis of both cytokines. These data indicate that antibacterial agents may modify acute-phase inflammatory responses through their effects on cytokine synthesis by monocytes.

scholarly journals Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis

2011 ◽  
Vol 208 (2) ◽  
pp. 217-225 ◽  
Author(s):  
Saskia C.A. de Jager ◽  
Beatriz Bermúdez ◽  
Ilze Bot ◽  
Rory R. Koenen ◽  
Martine Bot ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Phase ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Density Lipoprotein ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Differentiation Factor ◽  
Macrophage Chemotaxis

Growth differentiation factor (GDF) 15 is a member of the transforming growth factor β (TGF-β) superfamily, which operates in acute phase responses through a currently unknown receptor. Elevated GDF-15 serum levels were recently identified as a risk factor for acute coronary syndromes. We show that GDF-15 expression is up-regulated as disease progresses in murine atherosclerosis and primarily colocalizes with plaque macrophages. Hematopoietic GDF-15 deficiency in low density lipoprotein receptor−/− mice led to impaired initial lesion formation and increased collagen in later lesions. Although lesion burden in GDF-15−/− chimeras was unaltered, plaques had reduced macrophage infiltrates and decreased necrotic core formation, all features of improved plaque stability. In vitro studies pointed to a TGFβRII-dependent regulatory role of GDF-15 in cell death regulation. Importantly, GDF-15−/− macrophages displayed reduced CCR2 expression, whereas GDF-15 promoted macrophage chemotaxis in a strictly CCR2- and TGFβRII-dependent manner, a phenomenon which was not observed in G protein–coupled receptor kinase 2+/− macrophages. In conclusion, GDF-15 deletion has a beneficial effect both in early and later atherosclerosis by inhibition of CCR2-mediated chemotaxis and by modulating cell death. Our study is the first to identify GDF-15 as an acute phase modifier of CCR2/TGFβRII-dependent inflammatory responses to vascular injury.

scholarly journals Tumor-B-Cell Interactions Promote Isotype Switching to an Immunosuppressive IgG4 Antibody Response Through Upregulation of IL-10 in Triple Negative Breast Cancers

2021 ◽  
Author(s):  
Nicole J. Toney ◽  
Lynn M. Opdenaker ◽  
Kader Cicek ◽  
Holly Archinal ◽  
Lisa Frerichs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
B Cells ◽  
Triple Negative ◽  
Immune Escape ◽  
Inflammatory Responses ◽  
Dependent Manner ◽  
Th2 Cytokines ◽  
Class Switching ◽  
Isotype Switching

Abstract Background: Triple negative breast cancer (TNBC) is an aggressive breast cancer for which there is currently no targeted therapy. Tumor-infiltrating B-cells (TIB) have been observed in tumor tissues of TNBC patients, but their functional role is unclear. IgG4 is one of four antibody subclasses of IgG expressed and secreted by B cells. Unlike other IgG isotypes, IgG4 has an immunosuppressive function and is induced by Th2-type cytokines. In cancers such as melanoma, IgG4 has been linked with advanced disease and poor patient survival. Therefore, we sought to determine the role of IgG4 in TNBC. Methods: We performed co-culture assays to examine expression of Th2 cytokines by TNBC cells with and without the presence of B cells. We also performed in vitro class switching experiments with peripheral B cells with and without co-culture with TNBC cells in the presence or absence of an IL-10 blocking antibody. We examined expression of CD20 + TIB, IgG4 and Th2 cytokines by immunohistochemistry in 152 TNBC samples. Statistical analysis was done using Log-Rank and Cox-proportional hazards tests. Results: Our findings indicate that B cells interact with TNBC to drive chronic inflammatory responses through increased expression of inflammatory cytokines including the TH2 cytokines IL-4 and IL-10. In vitro class switching studies show that interactions between TNBC cell lines and B cells drive isotype switching to the IgG4 isotype in an IL-10 dependent manner. In patient tissues, expression of IgG4 correlates with CD20 and tumor expression of IL-10. Both IgG4 and tumor IL-10 are associated to shorter recurrence free survival (RFS) and overall survival (OS) in TNBC. In a multi-variant analysis, IL-10 was associated with poor outcomes indicating that tumor IL-10 may drive immune escape. Conclusions: These findings indicate that interactions between TIB and TNBC results in activation of chronic inflammatory signals that suppress antibody driven immune responses

scholarly journals Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury

2019 ◽  
Author(s):  
Mengya Jiao ◽  
Xiangyong Li ◽  
Xiaodi Wang ◽  
Liying Chen ◽  
Baohong Yuan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Brain Injury ◽  
Neurotrophic Factor ◽  
Inflammatory Responses ◽  
Neuroprotective Effect ◽  
Brain Infarction ◽  
Neurological Deficits ◽  
Dependent Manner ◽  
Ischemic Brain

Abstract Background: Interleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action. Methods: The brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia, and treated with IL-33 at a dose of 0.2 μg/day i.p. for three days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells, cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes. Results: The expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 d after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation. Conclusions: The activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy

2019 ◽  
Vol 116 (3) ◽  
pp. 576-591 ◽  
Author(s):  
Panagiotis Efentakis ◽  
Aimilia Varela ◽  
Evangelia Chavdoula ◽  
Fragiska Sigala ◽  
Despina Sanoudou ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Female Breast Cancer ◽  
Bolus Administration ◽  
Dependent Manner ◽  
In Vivo Experiments ◽  
Doxorubicin Cardiotoxicity ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Abstract Aims Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity. Methods and results Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN−/−) mice were assigned to PLN−/−/Control (N/S-0.9%), PLN−/−/DXR (18 mg/kg), and PLN−/−/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan’s cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN−/− mice. Levosimendan’s cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload. Conclusion Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.

scholarly journals Interleukin-1β, but not interleukin-6, enhances renal and systemic endothelin production in vivo

2008 ◽  
Vol 295 (2) ◽  
pp. F446-F453 ◽  
Author(s):  
Erika I. Boesen ◽  
Jennifer M. Sasser ◽  
Mohamed A. Saleh ◽  
William A. Potter ◽  
Mandy Woods ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Excretion Rate ◽  
Collecting Duct ◽  
Cell Types ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Subcutaneous Infusion ◽  
Medullary Collecting Duct

The inflammatory cytokines IL-1β and IL-6 have been shown to stimulate production of endothelin-1 (ET-1) by several cell types in vitro, but their effects on renal ET-1 production in vivo are not known. To test whether IL-1β and IL-6 stimulate renal ET-1 production and release in vivo, urine was collected from male C57BL/6 mice over 24-h periods at baseline and on days 7 and 14 of a 14-day subcutaneous infusion of IL-1β (10 ng/h), IL-6 (16 ng/h), or vehicle. By day 14, plasma ET-1 was significantly increased by IL-1β infusion (1.7 ± 0.1 vs. 0.8 ± 0.1 pg/ml for vehicle, P < 0.001). Compared with vehicle infusion, IL-1β infusion induced significant increases in urinary ET-1 excretion rate and urine flow but did not affect conscious mean arterial pressure (telemetry). IL-1β infusion significantly increased renal cortical and medullary IL-1β content (ELISA) and prepro-ET-1 mRNA expression (quantitative real-time PCR). In contrast, 14 days of IL-6 infusion had no significant effect on plasma ET-1 or urinary ET-1 excretion rate. To determine whether IL-1β stimulates ET-1 release via activation of NF-κB, inner medullary collecting duct (IMCD-3) cells were incubated for 24 h with IL-1β, and ET-1 release and NF-κB activation were measured (ELISA). IL-1β activated NF-κB and increased ET-1 release in a concentration-dependent manner. The effect of IL-1β on ET-1 release could be partially inhibited by pretreatment of IMCD-3 cells with an inhibitor of NF-κB activation (BAY 11-7082). These results indicate that IL-1β stimulates renal and systemic ET-1 production in vivo, providing further evidence that ET-1 participates in inflammatory responses.

Abstract 354: Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Robert A Campbell ◽  
Adriana Vieira-de-Abreu ◽  
Jesse W Rowley ◽  
Zechariah G Franks ◽  
Matthew T Rondina ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Inflammatory Responses ◽  
Vascular Diseases ◽  
Clot Formation ◽  
Clot Lysis ◽  
Dependent Manner ◽  
Plasma Clot ◽  
Monocyte Chemoattractant Protein 1

Objective: Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine if clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases. Approach and Results: We performed Next Generation RNA sequencing on monocytes extracted from whole blood clots. Thousands of mRNAs were differentially expressed by monocytes from clotted versus unclotted whole blood, including upregulation of interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1). Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in LPS-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent, but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (i.e., 1-2 hours) reduced the synthesis of IL-8 and MCP-1, while delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1. Conclusions: These findings demonstrate that clots are potent inducers of monocyte gene expression, and that timely fibrinolysis attenuates inflammatory responses. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically-proven efficacy of fibrinolytic drug treatment within hours of stroke onset.

Chemerin Bioactivity Is Regulated by Factor XIa: A Novel Interface Linking Between Coagulation, Hemostasis and Immunity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2258-2258
Author(s):  
Yasuto Yamaguchi ◽  
John Morser ◽  
Lawrence L. Leung
Keyword(s):  
Mass Spectroscopy ◽  
Time Course ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Proteolytic Processing ◽  
Cathepsin G ◽  
Dependent Manner ◽  
Factor Xia

Abstract Abstract 2258 Proteolytic modulation of chemokines by extracellular proteases, either released upon leukocyte degranulation or activated by the coagulation and fibrinolytic cascades, plays an important role in inflammation and immunity. Chemerin is a novel chemoattractant involved in innate and adaptive immunity and adipogenic differentiation via its receptor, CMKLR1, expressed on dendritic cells, macrophages and adipocytes. Chemerin circulates as an inactive precursor (chem163S) in blood whose bioactivity is regulated through proteolytic processing at its C-terminus. The most potent form of chemerin (chem157S) can be generated from chem163S in vitro by elastase directly or by sequential cleavages by plasmin to chem158K and then plasma carboxypeptidase-2 (CPB2, also termed thrombin-activatable fibrinolysis inhibitor TAFIa) or CPN to chem157S. Thus proteolytic processing is essential for chemerin activation. We have recently developed specific ELISAs for chem163S, 158K and 157S and showed that chem158K is present in plasma at a low level compared to chem163S. In contrast chem158K is the dominant form in synovial fluids of patients with inflammatory arthritis, suggesting that cleavage of chem163S at position 158K is a major step in the activation of chemerin in vivo. Although chem158K is present in vivo, it is unknown if it is generated by plasmin with a second cleavage by CPB2 or CPN to generate the active isoform, chem157S, as CPB2 inhibits plasmin generation. In this study we screened a panel of 21 proteases involved in coagulation, fibrinolysis and inflammation to determine which one could cleave the chemerin precursor chem163S to modulate its bioactivity. We carried out in vitro enzyme assays using 100 nM enzyme and 10 μM chem163S as a substrate, determining the results by SDS-PAGE and mass spectroscopy. Among the 21 proteases tested, cathepsin G, elastase, tryptase, plasmin, chymase, protease 3 and factor XIa could cleave chem163S. Mass spectroscopy identified tryptase, plasmin and factor XIa as enzymes that can digest chem163S to generate chem158K. Based on our previous observation that platelets are a rich cellular source of chemerin and release partially cleaved chemerin upon thrombin activation, we focused on factor XIa and compared its potency to plasmin. Factor XIa converted chem163S into chem158K in a dose-dependent manner whereas incubation with high concentrations of plasmin (300 nM) resulted in production of a non-specific smaller fragment, showing that the specificity of factor XIa was better than that of plasmin. Time-course studies showed that factor XIa and plasmin cleaved chem163S at comparable rates. Finally, we found that the fraction of chem158K to levels of total chemerin as determined by ELISA in factor XI-deficient plasma was lower than that in factor II-, IX-, X-deficient plasmas as well as normal pooled plasma. These data demonstrated that factor XIa could be the enzyme responsible for the first step of chemerin activation in the plasma compartment, ultimately leading to downstream inflammatory responses and provide a novel molecular link between coagulation, hemostasis and immunity. Disclosures: No relevant conflicts of interest to declare.

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