Non-immune functions of inflammatory cytokines targeted by anti-psoriatic biologics: a review

Antimicrobial peptides, also known as host defence peptides, are immunomodulatory molecules required to resolve infections. Antimicrobial peptides and proteins (APPs) are important in the control of infections in the lungs. Despite evidence that APPs exhibit a wide range of immune functions and modulate inflammation, the effect of inflammatory cytokines on the expression of APPs is not completely defined. In this study, we profiled the expression of 39 different APPs in human bronchial epithelial cells (HBEC) using Slow Off-rate Modified Aptamer (SOMAmer)-based protein array, in the presence and absence of three different inflammatory cytokines (IL-17, TNF and IFN-γ). Expression of 13 different APPs was altered in response to IL-17, TNF or IFN-γ. Independent validations of selected proteins from the proteomics screen i.e., those that were significantly enhanced by >2-fold change (p < 0.01) using western blots conclusively demonstrated that inflammatory cytokines alter the expression of APPs differentially. For example, the abundance of cathepsin S was enhanced by only IFN-γ, whereas lipocalin-2 was increased by IL-17 alone. Abundance of elafin increased in presence of IL-17 or TNF, but decreased in response to IFN-γ. Whereas the abundance of cathepsin V decreased following stimulation with IL-17, TNF and IFN-γ. The results of this study demonstrate that inflammatory cytokines alter the expression of APPs disparately. This suggests that the composition of the inflammatory cytokine milieu may influence APPs abundance and thus alter the processes required for infection control and regulation of inflammation in the lungs.

Download Full-text

A Novel Strategy for the Treatment of Acute Graft-Versus-Host Disease Using the Adsorbent To Remove Excessive Inflammatory Cytokines.

Blood ◽

10.1182/blood.v110.11.5001.5001 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5001-5001

Author(s):

Akiyoshi Takami ◽

Takanori Teshima ◽

Koshin Ushizaki ◽

Takumi Taniguchi ◽

Tohru Endo ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Graft Versus Host Disease ◽

Immune Functions ◽

Serum Samples ◽

Host Disease ◽

Graft Versus Host ◽

Extracorporeal Blood Purification ◽

Control Serum ◽

The Mean ◽

Acute Graft

Abstract Acute graft-versus-host disease (aGVHD) remains the major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). Previous studies show that inflammatory cytokines such as tumor necrosis factor alfa (TNFα), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-18 (IL-18) are involved in the pathogenesis of aGVHD, and that the excess of these cytokines is associated with severity and mortality of aGVHD. We hypothesized that removal of these excessive cytokines from patients’ blood at the onset of aGVHD might improve the treatment outcome. A novel absorbent CTR can effectively adsorb small- to middle-sized proteins like cytokines and enterotoxins in vitro. In view of future exploitation of extracorporeal treatment using CTR column, we tested whether CTR could remove these inflammatory cytokines from blood. When the serum containing a mix of recombinant cytokines was incubated with a CTR adsorbent for 2 hrs, 55% of TNFα, 81% of IL-6, 83% of IL-8, and 22% of IL-18 were successfully removed. Next, we measured TNFα, soluble TNFα receptor 1 (TNFR1), IL-6, IL-8, and IL-18 levels in serum samples obtained from 5 patients (median age 38y, range 26–63y) who underwent myeloablative SCT in 4 and non-myeloablative SCT in 1. AGVHD developed in 2 with grade 3 and in 3 with grade 2. When cytokine levels in patients were expressed as a ratio to the mean cytokine level in control serum samples obtained from three healthy individuals, the mean ratios of TNFα, TNFR1, IL-6, IL-8, and IL-18 at the onset of aGVHD were 6.0 (range, 1.2–12.0), 6.5 (2.5–9.0), 274 (3.5–651), 48.3 (11.3–75.2), and 6.7 (3.2–10.8). The CTR adsorption considerably reduced the concentrations of these cytokines except for IL-18 (Figure 1). The adsorption rates of these cytokines were 64% for TNFα, 48% for TNFR1, 59% for IL-6, more than 94% for IL-8, and 0% for IL-18. The efficient removal of inflammatory cytokines suggests that extracorporeal blood purification with CTR column may be effective in the treatment of aGVHD. This treatment strategy may be promising because it essentially has no deleterious effects on immune functions of SCT recipients unlike other GVHD treatments. Figure Figure

Download Full-text

Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia

10.21203/rs.2.18935/v1 ◽

2019 ◽

Author(s):

Sawako Shindo ◽

Shih-Heng Chen ◽

Saki Gotoh ◽

Kosuke Yokobori ◽

Hao Hu ◽

...

Keyword(s):

Estrogen Receptor ◽

Inflammatory Cytokines ◽

Estrogen Receptor Α ◽

Microglia Activation ◽

Immune Functions ◽

Protein Levels ◽

Brain Extracts ◽

Anti Inflammatory ◽

The Brain ◽

Pro Inflammatory Cytokines

Abstract Background Estrogen has been suggested to regulate anti-inflammatory signaling in brain microglia through estrogen receptor α (ERα), the only resident immune cells of the brain. The mechanism of how ERα regulates is not well understood. Previously, ERα is phosphorylated at Ser216 in mouse neutrophils, regulating their infiltration into the uterus. Therefore, ERα has now been examined as to its phosphorylation in microglia to regulate their inflammatory functions.MethodsAn antibody against an anti-phospho-S216 peptide of ERα (αP-S216) was used for double immunofluorescence staining to detect to ERα in cultured microglia. A knock-in (KI) mouse line bearing the phosphorylation-blocked ERα mutation S216A (ERα KI) was generated to examine whether this phosphorylation regulate immune functions of microglia.ResultsPhosphorylated ERα at Ser216 was present in microglia but not astrocytes. Staining with an anti-Iba-1 antibody showed that microglia activation was augmented in substantial nigra of ERα KI brains. Lipopolysaccharide (LPS) treatments aggravated microglia activation in ERα KI brains, pro-inflammatory cytokines were increased while anti-inflammatory cytokines were decreased at mRNA and protein levels in whole brain extracts. These increases and decreases of cytokine proteins were also observed in LPS-treated microglia cultured from brains of ERα KI neonates. FACS analysis revealed that ERα KI mutation increased number of IL-6 producing microglia and apoptosis. ERα KI mice decreased motor connection ability in Rotarod tests.ConclusionsBlocking of Ser216 phosphorylation aggravated microglia activation and inflammation of mouse brain, thus confirming that phosphorylated ERα exerts anti-inflammatory functions. ERα KI mice enable us to further investigate the mechanism by which phosphorylated ERα regulates brain immunity and inflammation.

Download Full-text

Leucine-Rich Repeat Kinase 2 Controls Inflammatory Cytokines Production through NF-κB Phosphorylation and Antigen Presentation in Bone Marrow-Derived Dendritic Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21051890 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1890

Author(s):

Makoto Kubo ◽

Ryuichi Nagashima ◽

Mitsue Kurihara ◽

Fumitaka Kawakami ◽

Tatsunori Maekawa ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Antigen Presentation ◽

Inflammatory Cytokines ◽

Immune Functions ◽

Leucine Rich Repeat ◽

Gm Csf ◽

Macrophage Colony ◽

Antigen Presenting

Leucine-rich repeat kinase 2 (LRRK2) is the causal molecule of familial Parkinson’s disease. Although the characteristics of LRRK2 have gradually been revealed, its true physiological functions remain unknown. LRRK2 is highly expressed in immune cells such as B2 cells and macrophages, suggesting that it plays important roles in the immune system. In the present study, we investigate the roles of LRRK2 in the immune functions of dendritic cells (DCs). Bone marrow-derived DCs from both C57BL/6 wild-type (WT) and LRRK2 knockout (KO) mice were induced by culture with granulocyte/macrophage-colony stimulating factor (GM/CSF) in vitro. We observed the differentiation of DCs, the phosphorylation of the transcriptional factors NF-κB, Erk1/2, and p-38 after lipopolysaccharide (LPS) stimulation and antigen-presenting ability by flow cytometry. We also analyzed the production of inflammatory cytokines by ELISA. During the observation period, there was no difference in DC differentiation between WT and LRRK2-KO mice. After LPS stimulation, phosphorylation of NF-κB was significantly increased in DCs from the KO mice. Large amounts of inflammatory cytokines were produced by DCs from KO mice after both stimulation with LPS and infection with Leishmania. CD4+ T-cells isolated from antigen-immunized mice proliferated to a significantly greater degree upon coculture with antigen-stimulated DCs from KO mice than upon coculture with DCs from WT mice. These results suggest that LRRK2 may play important roles in signal transduction and antigen presentation by DCs.

Download Full-text

Serum Levels of IL-12, IL-6, IL-10, IL-17 and IFN-γ in Female Students with Vitamin D Deficiency

10.21203/rs.3.rs-832276/v1 ◽

2021 ◽

Author(s):

Gholamreza Asadikaram ◽

Zahra Jamali ◽

Somayeh Igder ◽

Saeedeh Nabati ◽

Vahid Bagheri ◽

...

Keyword(s):

Vitamin D ◽

Inflammatory Cytokines ◽

Serum Levels ◽

Female Students ◽

Control Group ◽

Case Group ◽

Immune Functions ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D ◽

Regulatory Effects

Abstract Background: Several studies demonstrated the regulatory effects of vitamin D3 on the immune system. The aim of this study was to investigate the serum levels of IL-12, IL-6, IL-10, IL-17 and IFN-g cytokines in 11-17 year-old female students with 25-hydroxyvitamin D3 (25-(OH) D3) (VitD3) deficiency. Methods: 100 subjects with VitD3 deficiency were selected as the case group and an equal number of individuals with sufficient levels of VitD3 were selected as a control group. The serum levels of IL-10, IL-6, IL-12, IFN-g and IL-17 were measured by ELISA method. Results: The results showed that the serum concentrations of IL-12 (P= 0.005) and IFN-g (P= 0.019) were significantly lower in VitD3-deficient group compared to control group. There were no significant differences in serum levels of IL-6 (P= 0.66), IL-10 (P= 0.647) and IL-17 (P= 0.159) between cases and controls.Conclusion: These results suggest that VitD3deficiency may result in decreased inflammatory cytokines production, which are required for proper immune functions. However, the effects of VitD3 on IL-6 and IL-17A, as the pro-inflammatory and IL-10, as anti-inflammatory cytokines needs more investigations.

Download Full-text

Gua Sha, a press-stroke treatment of the skin, boosts the immune response to intradermal vaccination

PeerJ ◽

10.7717/peerj.2451 ◽

2016 ◽

Vol 4 ◽

pp. e2451 ◽

Cited By ~ 2

Author(s):

Tingting Chen ◽

Ninghua Liu ◽

Jinxuan Liu ◽

Xiaoying Zhang ◽

Zhen Huang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Systemic Circulation ◽

The Body ◽

Therapeutic Effects ◽

Immune Functions ◽

Intradermal Vaccination ◽

Stroke Treatment ◽

Gua Sha ◽

Intradermal Delivery ◽

Immunosuppressive Cytokines

ObjectiveThe skin is an important immunological barrier of the body as well as an optimal route for vaccine administration. Gua Sha, which involves press-stroke treatment of the skin, is an effective folk therapy, widely accepted in East Asia, for various symptoms; however, the mechanisms underlying its therapeutic effects have not been clarified. We investigated the influence of Gua Sha on the immunological features of the skin.MethodsGua Sha was performed on BALB/c mice and the effects were evaluated using anatomical, histological, and cytometric methods as well as cytokine determination locally and systemically. The effect on intradermal vaccination was assessed with antigen-specific subtype antibody responses.ResultsBlood vessel expansion, erythrocyte extravasation, and increased ratios of immune active cells were observed in the skin tissue following the treatment. Pro-inflammatory cytokines were up-regulated, and immunosuppressive cytokines, down-regulated, in the treated and untreated skin and systemic circulation; no obvious variations were detected in case of anti-inflammatory cytokines. Interestingly, intradermal delivery of a model vaccine following Gua Sha induced about three-fold higher IgG titers with a more Th1-biased antibody subtype profile.ConclusionGua Sha treatment can up-regulate the innate and adaptive immune functions of the skin and boost the response against intradermal antigens. Thus, Gua Sha may serve as a safe, inexpensive, and independent physical adjuvant for intradermal vaccination.

Download Full-text

Hedgehog dysregulation contributes to tissue-specific inflammaging of resident macrophages

10.1101/2020.08.16.253237 ◽

2020 ◽

Author(s):

Mahamat Babagana ◽

Kyu-Seon Oh ◽

Sayantan Chakraborty ◽

Alicja Pacholewska ◽

Mohammad Aqdas ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Innate Immune ◽

Sterile Inflammation ◽

Low Grade ◽

Immune Functions ◽

Tissue Specific ◽

Physiological Aging ◽

Age Related ◽

Hh Signaling

AbstractAge-associated low-grade sterile inflammation, commonly referred to as inflammaging, is a recognized hallmark of aging, which contributes to many age-related diseases. While tissue-resident macrophages are innate immune cells that secrete many types of inflammatory cytokines in response to various stimuli, it is not clear whether they have a role in driving inflammaging. Here we characterized the transcriptional changes associated with physiological aging in mouse resident macrophage populations across different tissues and sexes. Although the age-related transcriptomic signatures of resident macrophages were strikingly tissue-specific, the differentially expressed genes were collectively enriched for those with important innate immune functions such as antigen presentation, cytokine production, and cell adhesion. The brain-resident microglia had the most wide-ranging age-related alterations, with compromised expression of tissue-specific genes and relatively exaggerated responses to endotoxin stimulation. Despite the tissue-specific patterns of aging transcriptomes, components of the hedgehog (Hh) signaling pathway were decreased in aged macrophages across multiple tissues. In vivo suppression of Hh signaling in young animals increased the expression of pro-inflammatory cytokines, while in vitro activation of Hh signaling in old macrophages, in turn, suppressed the expression of these inflammatory cytokines. This suggests that hedgehog signaling could be a potential intervention axis for mitigating age-associated inflammation and related diseases. Overall, our data represent a resourceful catalog of tissue-specific and sex-specific transcriptomic changes in resident macrophages of peritoneum, liver, and brain, during physiological aging.

Download Full-text

Balance Between Pro- and Anti-Inflammatory Cytokines in Mice Treated WithCentruroides noxiusScorpion Venom

Mediators of Inflammation ◽

10.1155/mi/2006/54273 ◽

2006 ◽

Vol 2006 ◽

pp. 1-11 ◽

Cited By ~ 19

Author(s):

Vera L. Petricevich

Keyword(s):

Inflammatory Cytokines ◽

Time Course ◽

Lethal Factor ◽

Serum Levels ◽

Enzyme Linked Immunosorbent Assay ◽

Immune Functions ◽

Inflammatory Status ◽

Cytokine Levels ◽

Anti Inflammatory

CSV consists of a very complex of molecules and demonstrates significant cellular activities capable of stimulating immune functions in vivo. The purpose of this study was to analyze the effects of CSV on sex, weight, route of injection and the balance of pro- and anti-inflammatory cytokines in mice. The susceptibility and route of injection were analyzed by lethal (LD50) determination. The effects of CSV were also analyzed in blood from immunized mice using detection by means of antibodies and mediators production. Several functional bioassays were employed: TNF activity was assayed by measuring its cytotoxic activity in L929 cells, and other cytokines were assayed by enzyme-linked immunosorbent assay, whereas nitric oxide levels were detected by Griess colorimetric reactions in sera from BALB/c mice. After injecting subcutaneously, the LD50presented an increase of the CSV correlation and similar levels of susceptibility were obtained for female and male from BALB/c mice. Significant differences were observed in the time-course of cytokine levels. The balance of pro- and anti-inflammatory cytokines TNF/IL-10 and IL-6/IL-10 ratios were significantly higher in injected mice group when compared with those obtained for non-injected group. The CSV is poor in antigenic composition and it is difficult to get antibodies specific to neutralizing the lethal factor. The effect of immunization with 0.5 LD50of CSV on the balance of pro- and anti-inflammatory cytokines was measured. The maximum levels of TNF and IL-6, IFN-γand NO were observed on days 7 and 21 after immunization, respectively. IL-10 levels peaked between days 21 and 28 after immunization with CSV. With respect, to balance of pro- and anti-inflammatory cytokines it was possible to observe that negative correlation between serum levels of IL-6/IL-10 and TNF/IL-10 exists. These ratios may possibly reflect the balance of pro- and anti-inflammatory cytokines in serum, which may by manifested in the inflammatory status during the envenoming processes. In conclusion, an increase in the serum levels of TNF and IL-6 may be a useful marker for scorpion envenomation.

Download Full-text

The Role of Inflammatory Cytokines, the RANKL/OPG Axis, and the Immunoskeletal Interface in Physiological Bone Turnover and Osteoporosis

Scientifica ◽

10.1155/2013/125705 ◽

2013 ◽

Vol 2013 ◽

pp. 1-29 ◽

Cited By ~ 59

Author(s):

M. Neale Weitzmann

Keyword(s):

Bone Turnover ◽

Inflammatory Cytokines ◽

Osteoclast Formation ◽

The Body ◽

Immune Functions ◽

Regulatory Processes ◽

Downstream Effector ◽

Receptor Activator ◽

Skeletal Integrity

Although it has long been recognized that inflammation, a consequence of immune-driven processes, significantly impacts bone turnover, the degree of centralization of skeletal and immune functions has begun to be dissected only recently. It is now recognized that formation of osteoclasts, the bone resorbing cells of the body, is centered on the key osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL). Although numerous inflammatory cytokines are now recognized to promote osteoclast formation and skeletal degradation, with just a few exceptions, RANKL is now considered to be the final downstream effector cytokine that drives osteoclastogenesis and regulates osteoclastic bone resorption. The biological activity of RANKL is moderated by its physiological decoy receptor, osteoprotegerin (OPG). New discoveries concerning the sources and regulation of RANKL and OPG in physiological bone turnover as well as under pathological (osteoporotic) conditions continue to be made, opening a window to the complex regulatory processes that control skeletal integrity and the depth of integration of the skeleton within the immune response. This paper will examine the interconnection between bone turnover and the immune system and the implications thereof for physiological and pathological bone turnover.

Download Full-text

Recent insights into the role of dipeptidyl aminopeptidase IV (DPIV) and aminopeptidase N (APN) families in immune functions

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2009.063 ◽

2009 ◽

Vol 47 (3) ◽

Cited By ~ 45

Author(s):

Siegfried Ansorge ◽

Ute Bank ◽

Anke Heimburg ◽

Martin Helmuth ◽

Gudrun Koch ◽

...

Keyword(s):

Dna Synthesis ◽

Inflammatory Cytokines ◽

Cell Cycle Progression ◽

Cytokine Production ◽

Immune Functions ◽

Selective Inhibitors ◽

Inhibition Of Proliferation ◽

Functional Changes ◽

Cellular Effects

Abstract: In the past, different research groups could show that treatment of immune cells with inhibitors of post-proline splitting dipeptidyl aminopeptidases leads to functional changes in the immune system consistent with immunosuppression. This is due to the inhibition of proliferation of lymphocytes and the production of inflammatory cytokines of the TH: Summarizing data obtained from the usage of different non-selective and selective inhibitors of DPIV, DP8/9, FAP, and DPII, this review provides evidence that in addition to DPIV, DP8/9 also regulate the immune response via modulation of cell cycle progression and cytokine production. The strongest and most consistent effects in vitro were, however, observed with non-selective inhibitors for the suppression of DNA synthesis and cytokine production. Similar effects were provoked by APN inhibitors, which were also found to suppress DNA synthesis and the production of inflammatory cytokines in vitro. However, different mechanisms and signaling pathways appear to mediate the cellular effects resulting from the inhibition of either APN or DPIV family members. In particular, members of the APN family uniquely influence the function of CD4Clin Chem Lab Med 2009;47:253–61.

Download Full-text