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16 pages, 4330 KiB

Open AccessArticle

Protective Effects of Sophoraflavanone G by Inhibiting TNF-α-Induced MMP-9-Mediated Events in Brain Microvascular Endothelial Cells

by Tsong-Hai Lee, Jiun-Liang Chen, Ming-Ming Tsai, Yi-Hsuan Wu, Hui-Ching Tseng, Li-Ching Cheng, Velayuthaprabhu Shanmugam and Hsi-Lung Hsieh

Int. J. Mol. Sci. 2024, 25(1), 283; https://doi.org/10.3390/ijms25010283 - 24 Dec 2023

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Abstract

The regulation of matrix metalloproteinases (MMPs), especially MMP-9, has a critical role in both physiological and pathological events in the central nervous system (CNS). MMP-9 is an indicator of inflammation that triggers several CNS disorders, including neurodegeneration. Tumor necrosis factor-α (TNF-α) has the [...] Read more.

The regulation of matrix metalloproteinases (MMPs), especially MMP-9, has a critical role in both physiological and pathological events in the central nervous system (CNS). MMP-9 is an indicator of inflammation that triggers several CNS disorders, including neurodegeneration. Tumor necrosis factor-α (TNF-α) has the ability to stimulate the production of different inflammatory factors, including MMP-9, in several conditions. Numerous phytochemicals are hypothesized to mitigate inflammation, including the CNS. Among them, a flavonoid compound, sophoraflavanone G (SG), found in Sophora flavescens has been found to possess several medicinal properties, including anti-bacterial and anti-inflammatory effects. In this study, mouse brain microvascular endothelial cells (bMECs) were used to explore TNF-α-induced MMP-9 signaling. The effects of SG on TNF-α-induced MMP-9 expression and its mechanisms were further evaluated. Our study revealed that the expression of MMP-9 in bMECs was stimulated by TNF-α through the activation of ERK1/2, p38 MAPK, and JNK1/2 via the TNF receptor (TNFR) with a connection to the NF-κB signaling pathway. Moreover, we found that SG can interact with the TNFR. The upregulation of MMP-9 by TNF-α may lead to the disruption of zonula occludens-1 (ZO-1), which can be mitigated by SG administration. These findings provide evidence that SG may possess neuroprotective properties by inhibiting the signaling pathways associated with TNFR-mediated MMP-9 expression and the subsequent disruption of tight junctions in brain microvascular endothelial cells. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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16 pages, 13895 KiB

Open AccessArticle

IL-6 Mutation Attenuates Liver Injury Caused by Aeromonas hydrophila Infection by Reducing Oxidative Stress in Zebrafish

by Wenya Zhai, Zhensheng Wang, Canxun Ye, Lan Ke, Huanling Wang and Hong Liu

Int. J. Mol. Sci. 2023, 24(24), 17215; https://doi.org/10.3390/ijms242417215 - 07 Dec 2023

Viewed by 796

Abstract

Interleukin-6 (IL-6), a pleiotropic cytokine, plays a crucial role in acute stress induced by bacterial infection and is strongly associated with reactive oxygen species (ROS) production. However, the role of IL-6 in the liver of fish after Aeromonas hydrophila infection remains unclear. Therefore, [...] Read more.

Interleukin-6 (IL-6), a pleiotropic cytokine, plays a crucial role in acute stress induced by bacterial infection and is strongly associated with reactive oxygen species (ROS) production. However, the role of IL-6 in the liver of fish after Aeromonas hydrophila infection remains unclear. Therefore, this study constructed a zebrafish (Danio rerio) il-6 knockout line by CRISPR/Cas9 to investigate the function of IL-6 in the liver post bacterial infection. After infection with A. hydrophila, pathological observation showed that il-6^−/− zebrafish exhibited milder liver damage than wild-type (WT) zebrafish. Moreover, liver transcriptome sequencing revealed that 2432 genes were significantly up-regulated and 1706 genes were significantly down-regulated in il-6^−/− fish compared with WT fish after A. hydrophila infection. Further, gene ontology (GO) analysis showed that differentially expressed genes (DEGs) were significantly enriched in redox-related terms, including oxidoreductase activity, copper ion transport, etc. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that DEGs were significantly enriched in pathways such as the PPAR signaling pathway, suggesting that il-6 mutation has a significant effect on redox processes in the liver after A. hydrophila infection. Additionally, il-6^−/− zebrafish exhibited lower malondialdehyde (MDA) levels and higher superoxide dismutase (SOD) activities in the liver compared with WT zebrafish following A. hydrophila infection, indicating that IL-6 deficiency mitigates oxidative stress induced by A. hydrophila infection in the liver. These findings provide a basis for further studies on the role of IL-6 in regulating oxidative stress in response to bacterial infections. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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21 pages, 4885 KiB

Open AccessArticle

Investigating the Effects of a New Peptide, Derived from the Enterolobium contortisiliquum Proteinase Inhibitor (EcTI), on Inflammation, Remodeling, and Oxidative Stress in an Experimental Mouse Model of Asthma–Chronic Obstructive Pulmonary Disease Overlap (ACO)

by Jéssica Anastácia Silva Barbosa, Luana Laura Sales da Silva, Juliana Morelli Lopes Gonçalves João, Elaine Cristina de Campos, Silvia Fukuzaki, Leandro do Nascimento Camargo, Tabata Maruyama dos Santos, Henrique Tibucheski dos Santos, Suellen Karoline Moreira Bezerra, Beatriz Mangueira Saraiva-Romanholo, Fernanda Degobbi Tenório Quirino dos Santos Lopes, Camila Ramalho Bonturi, Maria Luiza Vilela Oliva, Edna Aparecida Leick, Renato Fraga Righetti and Iolanda de Fátima Lopes Calvo Tibério

Int. J. Mol. Sci. 2023, 24(19), 14710; https://doi.org/10.3390/ijms241914710 - 28 Sep 2023

Viewed by 1028

Abstract

The synthesized peptide derived from Enterolobium contortisiliquum (pep3-EcTI) has been associated with potent anti-inflammatory and antioxidant effects, and it may be a potential new treatment for asthma–COPD overlap—ACO). Purpose: To investigate the primary sequence effects of pep3-EcTI in an experimental ACO. BALB/c mice [...] Read more.

The synthesized peptide derived from Enterolobium contortisiliquum (pep3-EcTI) has been associated with potent anti-inflammatory and antioxidant effects, and it may be a potential new treatment for asthma–COPD overlap—ACO). Purpose: To investigate the primary sequence effects of pep3-EcTI in an experimental ACO. BALB/c mice were divided into eight groups: SAL (saline), OVA (ovalbumin), ELA (elastase), ACO (ovalbumin + elastase), ACO-pep3-EcTI (treated with inhibitor), ACO-DX (treated with dexamethasone), ACO-DX-pep3-EcTI (treated with dexamethasone and inhibitor), and SAL-pep3-EcTI (saline group treated with inhibitor). We evaluated the hyperresponsiveness to methacholine, exhaled nitric oxide, bronchoalveolar lavage fluid (BALF), mean linear intercept (Lm), inflammatory markers, tumor necrosis factor (TNF-α), interferon (IFN)), matrix metalloproteinases (MMPs), growth factor (TGF-β), collagen fibers, the oxidative stress marker inducible nitric oxide synthase (iNOS), transcription factors, and the signaling pathway NF-κB in the airways (AW) and alveolar septa (AS). Statistical analysis was conducted using one-way ANOVA and t-tests, significant when p < 0.05. ACO caused alterations in the airways and alveolar septa. Compared with SAL, ACO-pep3-EcTI reversed the changes in the percentage of resistance of the respiratory system (%Rrs), the elastance of the respiratory system (%Ers), tissue resistance (%Gtis), tissue elastance (%Htis), airway resistance (%Raw), Lm, exhaled nitric oxide (ENO), lymphocytes, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, TNF-α, INF-γ, MMP-12, transforming growth factor (TGF)-β, collagen fibers, and iNOS. ACO-DX reversed the changes in %Rrs, %Ers, %Gtis, %Htis, %Raw, total cells, eosinophils, neutrophils, lymphocytes, macrophages, IL-1β, IL-6, IL-10, IL-13, IL-17, TNF-α, INF-γ, MMP-12, TGF-β, collagen fibers, and iNOS. ACO-DX-pep3-EcTI reversed the changes, as was also observed for the pep3-EcTI and the ACO-DX-pep3-EcTI. Significance: The pep3-EcTI was revealed to be a promising strategy for the treatment of ACO, asthma, and COPD. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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26 pages, 4028 KiB

Open AccessArticle

Effects of a Peptide Derived from the Primary Sequence of a Kallikrein Inhibitor Isolated from Bauhinia bauhinioides (pep-BbKI) in an Asthma–COPD Overlap (ACO) Model

by Luana Laura Sales da Silva, Jéssica Anastácia Silva Barbosa, Juliana Morelli Lopes Gonçalves João, Silvia Fukuzaki, Leandro do Nascimento Camargo, Tabata Maruyama dos Santos, Elaine Cristina de Campos, Arthur Silva Costa, Beatriz Mangueira Saraiva-Romanholo, Suellen Karoline Moreira Bezerra, Fernanda Tenório Quirino dos Santos Lopes, Camila Ramalho Bonturi, Maria Luiza Vilela Oliva, Edna Aparecida Leick, Renato Fraga Righetti and Iolanda de Fátima Lopes Calvo Tibério

Int. J. Mol. Sci. 2023, 24(14), 11261; https://doi.org/10.3390/ijms241411261 - 09 Jul 2023

Cited by 2 | Viewed by 1204

Abstract

(1) There are several patients with asthma–COPD overlap (ACO). A peptide derived from the primary sequence of a kallikrein inhibitor isolated from Bauhinia bauhinioides (pep-BbKI) has potent anti-inflammatory and antioxidant effects. Purpose: To investigate the effects of pep-BbKI treatment in an ACO model [...] Read more.

(1) There are several patients with asthma–COPD overlap (ACO). A peptide derived from the primary sequence of a kallikrein inhibitor isolated from Bauhinia bauhinioides (pep-BbKI) has potent anti-inflammatory and antioxidant effects. Purpose: To investigate the effects of pep-BbKI treatment in an ACO model and compare them with those of corticosteroids. (2) BALB/c mice were divided into groups: SAL (saline), OVA (ovalbumin), ELA (elastase), ACO (ovalbumin + elastase), ACO-pep-BbKI (treated with inhibitor), ACO-DX (dexamethasone treatment), ACO-DX-pep-BbKI (both treatments), and SAL-pep-BbKI (saline group treated with inhibitor). We evaluated: hyperresponsiveness to methacholine, bronchoalveolar lavage fluid (BALF), exhaled nitric oxide (eNO), IL-1β, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, IFN-γ, TNF-α, MMP-9, MMP-12, TGF-β, collagen fibers, iNOS, eNO, linear mean intercept (Lm), and NF-κB in airways (AW) and alveolar septa (AS). (3) ACO-pep-BbKI reversed ACO alterations and was similar to SAL in all mechanical parameters, Lm, neutrophils, IL-5, IL-10, IL-17, IFN-γ, TNF-α, MMP-12 (AW), collagen fibers, iNOS (AW), and eNO (p > 0.05). ACO-DX reversed ACO alterations and was similar to SAL in all mechanical parameters, Lm, total cells and differentials, IL-1β(AS), IL-5 (AS), IL-6 (AS), IL-10 (AS), IL-13 (AS), IFN-γ, MMP-12 (AS), TGF-β (AS), collagen fibers (AW), iNOS, and eNO (p > 0.05). SAL was similar to SAL-pep-BbKI for all comparisons (p > 0.05). (4) Pep-BbKI was similar to dexamethasone in reducing the majority of alterations of this ACO model. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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15 pages, 2877 KiB

Open AccessArticle

Sex Differences in Sphingosine-1-Phosphate Levels Are Dependent on Ceramide Synthase 1 and Ceramidase in Lung Physiology and Tumor Conditions

by Michela Terlizzi, Chiara Colarusso, Giusy Ferraro, Anna Falanga, Maria Chiara Monti, Pasquale Somma, Ilaria De Rosa, Luigi Panico, Aldo Pinto and Rosalinda Sorrentino

Int. J. Mol. Sci. 2023, 24(13), 10841; https://doi.org/10.3390/ijms241310841 - 29 Jun 2023

Viewed by 1246

Abstract

Sex is a biological variable that can reflect clinical outcomes in terms of quality of life, therapy effectiveness, responsiveness and/or toxicity. Sphingosine-1-phosphate (S1P) is a lipidic mediator whose activity can be influenced by sex. To evaluate whether the S1P axis underlies sex ‘instructions’ [...] Read more.

Sex is a biological variable that can reflect clinical outcomes in terms of quality of life, therapy effectiveness, responsiveness and/or toxicity. Sphingosine-1-phosphate (S1P) is a lipidic mediator whose activity can be influenced by sex. To evaluate whether the S1P axis underlies sex ‘instructions’ in the lung during physiological and oncological lung conditions, sphingosine and S1P were quantified in the blood of healthy (H) volunteers, lung adenocarcinoma (ADK) and squamous cell carcinoma (SCC) patients of both sexes. S1P receptors and their metabolic enzymes were evaluated in the tissues. Circulating levels of S1P were similar among H female and male subjects and female SCC patients. Instead, male and female ADK patients had lower circulating S1P levels. S1P receptor 3 (S1PR3) was physiologically expressed in the lung, but it was overexpressed in male SCC, and female and male ADK, but not in female SCC patients, who showed a significantly reduced ceramide synthase 1 (CERS1) mRNA and an overexpression of the ceramidase (ASAH1) precursor in lung tumor tissues, compared to male SCC and both male and female ADK patients. These findings highlighted sex differences in S1P rheostat in pathological conditions, but not in physiological conditions, identifying S1P as a prognostic mediator depending on lung cancer histotype. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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23 pages, 2062 KiB

Open AccessArticle

Anti-Inflammatory Klotho Protein Serum Concentration Correlates with Interferon Gamma Expression Related to the Cellular Activity of Both NKT-like and T Cells in the Process of Human Aging

by Lucyna Kaszubowska, Jerzy Foerster, Jan Jacek Kaczor, Mateusz Jakub Karnia and Zbigniew Kmieć

Int. J. Mol. Sci. 2023, 24(9), 8393; https://doi.org/10.3390/ijms24098393 - 07 May 2023

Cited by 1 | Viewed by 1833

Abstract

Klotho is a beta-glucuronidase that reveals both anti-inflammatory and anti-oxidative properties that have been associated with mechanisms of aging. The study aimed to analyze the relationships between the serum concentration of soluble α-Klotho and cellular activity of two populations of lymphocytes; T and [...] Read more.

Klotho is a beta-glucuronidase that reveals both anti-inflammatory and anti-oxidative properties that have been associated with mechanisms of aging. The study aimed to analyze the relationships between the serum concentration of soluble α-Klotho and cellular activity of two populations of lymphocytes; T and NKT-like cells corresponding to the level of cytokine secretion; i.e., IFN-γ, TNF-α, and IL-6. The studied population comprised three age groups: young individuals (‘young’), seniors aged under 85 (‘old’), and seniors aged over 85 (‘oldest’). Both NKT-like and T cells were either non-cultured or cultured for 48 h and stimulated appropriately with IL-2, LPS or PMA with ionomycin to compare with unstimulated control cells. In all studied age groups non-cultured or cultured NKT-like cells revealed higher expressions of TNF-α, IL-6, and IFN-γ than T cells. α-Klotho concentration in serum decreased significantly in the process of aging. Intriguingly, only IFN-γ expression revealed a positive correlation with α-Klotho protein serum concentration in both non-cultured and cultured T and NKT-like cells. Since IFN-γ is engaged in the maintenance of immune homeostasis, the observed relationships may indicate the involvement of α-Klotho and cellular IFN-γ expression in the network of adaptive mechanisms developed during the process of human aging. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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16 pages, 3736 KiB

Open AccessArticle

Cell Intrinsic IL-38 Affects B Cell Differentiation and Antibody Production

by Arnaud Huard, Christian Wilmes, Anastasiia Kiprina, Christoph Netzer, Gaby Palmer, Bernhard Brüne and Andreas Weigert

Int. J. Mol. Sci. 2023, 24(6), 5676; https://doi.org/10.3390/ijms24065676 - 16 Mar 2023

Cited by 2 | Viewed by 1752

Abstract

IL-38 is an IL-1 family receptor antagonist with an emerging role in chronic inflammatory diseases. IL-38 expression has been mainly observed not only in epithelia, but also in cells of the immune system, including macrophages and B cells. Given the association of both [...] Read more.

IL-38 is an IL-1 family receptor antagonist with an emerging role in chronic inflammatory diseases. IL-38 expression has been mainly observed not only in epithelia, but also in cells of the immune system, including macrophages and B cells. Given the association of both IL-38 and B cells with chronic inflammation, we explored if IL-38 affects B cell biology. IL-38-deficient mice showed higher amounts of plasma cells (PC) in lymphoid organs but, conversely, lower levels of plasmatic antibody titers. Exploring underlying mechanisms in human B cells revealed that exogenously added IL-38 did not significantly affect early B cell activation or differentiation into plasma cells, even though IL-38 suppressed upregulation of CD38. Instead, IL-38 mRNA expression was transiently upregulated during the differentiation of human B cells to plasma cells in vitro, and knocking down IL-38 during early B cell differentiation increased plasma cell generation, while reducing antibody production, thus reproducing the murine phenotype. Although this endogenous role of IL-38 in B cell differentiation and antibody production did not align with an immunosuppressive function, autoantibody production induced in mice by repeated IL-18 injections was enhanced in an IL-38-deficient background. Taken together, our data suggest that cell-intrinsic IL-38 promotes antibody production at baseline but suppresses the production of autoantibodies in an inflammatory context, which may partially explain its protective role during chronic inflammation. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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Review

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Open AccessReview

Interaction between Selected Adipokines and Musculoskeletal and Cardiovascular Systems: A Review of Current Knowledge

by Olga Sierawska and Marek Sawczuk

Int. J. Mol. Sci. 2023, 24(24), 17287; https://doi.org/10.3390/ijms242417287 - 09 Dec 2023

Cited by 1 | Viewed by 819

Abstract

Adipokines are substances secreted by adipose tissue that are receiving increasing attention. The approach to adipose tissue has changed in recent years, and it is no longer looked at as just a storage organ but its secretion and how it influences systems in [...] Read more.

Adipokines are substances secreted by adipose tissue that are receiving increasing attention. The approach to adipose tissue has changed in recent years, and it is no longer looked at as just a storage organ but its secretion and how it influences systems in the human body are also looked at. The role of adipokine seems crucial in developing future therapies for pathologies of selected systems. In this study, we look at selected adipokines, leptin, adiponectin, chemerin, resistin, omentin-1, nesfatin, irisin-1, visfatin, apelin, vaspin, heparin-binding EGF-like growth factor (HB-EGF), and TGF-β2, and how they affect systems in the human body related to physical activity such as the musculoskeletal and cardiovascular systems. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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20 pages, 1354 KiB

Open AccessReview

Cytokines as Biomarkers for Evaluating Physical Exercise in Trained and Non-Trained Individuals: A Narrative Review

by Paulina Małkowska and Marek Sawczuk

Int. J. Mol. Sci. 2023, 24(13), 11156; https://doi.org/10.3390/ijms241311156 - 06 Jul 2023

Cited by 9 | Viewed by 3299

Abstract

Physical activity and exercise training have numerous health benefits, including the prevention and management of chronic diseases, improvement of cardiovascular health, and enhancement of mental well-being. However, the effectiveness of training programs can vary widely among individuals due to various factors, such as [...] Read more.

Physical activity and exercise training have numerous health benefits, including the prevention and management of chronic diseases, improvement of cardiovascular health, and enhancement of mental well-being. However, the effectiveness of training programs can vary widely among individuals due to various factors, such as genetics, lifestyle, and environment. Thus, identifying reliable biomarkers to evaluate physical training effectiveness and personalize training programs is crucial. Cytokines are signaling molecules produced by immune cells that play a vital role in inflammation and tissue repair. In recent years, there has been increasing interest in the potential use of cytokines as biomarkers for evaluating training effectiveness. This review article aims to provide an overview of cytokines, their potential as biomarkers, methods for measuring cytokine levels, and factors that can affect cytokine levels. The article also discusses the potential benefits of using cytokines as biomarkers, such as monitoring muscle damage and inflammation, and the potential for personalized training programs based on cytokine responses. We believe that the use of cytokines as biomarkers holds great promise for optimizing training programs and improving overall health outcomes. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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21 pages, 2390 KiB

Open AccessReview

Multiple Roles of the Stress Sensor GCN2 in Immune Cells

by Chenxu Zhao, Han Guo, Yangxiao Hou, Tong Lei, Dong Wei and Yong Zhao

Int. J. Mol. Sci. 2023, 24(5), 4285; https://doi.org/10.3390/ijms24054285 - 21 Feb 2023

Cited by 7 | Viewed by 3091

Abstract

The serine/threonine-protein kinase general control nonderepressible 2 (GCN2) is a well-known stress sensor that responds to amino acid starvation and other stresses, making it critical to the maintenance of cellular and organismal homeostasis. More than 20 years of research has revealed the molecular [...] Read more.

The serine/threonine-protein kinase general control nonderepressible 2 (GCN2) is a well-known stress sensor that responds to amino acid starvation and other stresses, making it critical to the maintenance of cellular and organismal homeostasis. More than 20 years of research has revealed the molecular structure/complex, inducers/regulators, intracellular signaling pathways and bio-functions of GCN2 in various biological processes, across an organism’s lifespan, and in many diseases. Accumulated studies have demonstrated that the GCN2 kinase is also closely involved in the immune system and in various immune-related diseases, such as GCN2 acts as an important regulatory molecule to control macrophage functional polarization and CD4⁺ T cell subset differentiation. Herein, we comprehensively summarize the biological functions of GCN2 and discuss its roles in the immune system, including innate and adaptive immune cells. We also discuss the antagonism of GCN2 and mTOR pathways in immune cells. A better understanding of GCN2′s functions and signaling pathways in the immune system under physiological, stressful, and pathological situations will be beneficial to the development of potential therapies for many immune-relevant diseases. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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Other

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14 pages, 1460 KiB

Open AccessBrief Report

Rethinking IL-1 Antagonism in Respiratory Viral Infections: A Role for IL-1 Signaling in the Development of Antiviral T Cell Immunity

by Bram Van Den Eeckhout, Marlies Ballegeer, Jozefien De Clercq, Elianne Burg, Xavier Saelens, Linos Vandekerckhove and Sarah Gerlo

Int. J. Mol. Sci. 2023, 24(21), 15770; https://doi.org/10.3390/ijms242115770 - 30 Oct 2023

Cited by 1 | Viewed by 882

Abstract

IL-1R integrates signals from IL-1α and IL-1β, and it is widely expressed across tissues and immune cell types. While the expression pattern and function of IL-1R within the innate immune system is well studied, its role in adaptive immunity, particularly within the CD8 [...] Read more.

IL-1R integrates signals from IL-1α and IL-1β, and it is widely expressed across tissues and immune cell types. While the expression pattern and function of IL-1R within the innate immune system is well studied, its role in adaptive immunity, particularly within the CD8 T cell compartment, remains underexplored. Here, we show that CD8 T cells dynamically upregulate IL-1R1 levels during priming by APCs, which correlates with their proliferation status and the acquisition of an effector phenotype. Notably, this IL-1 sensitivity persists in memory CD8 T cells of both mice and humans, influencing effector cytokine production upon TCR reactivation. Furthermore, our study highlights that antiviral effector and tissue-resident CD8 T cell responses against influenza A virus infection become impaired in the absence of IL-1 signaling. Altogether, these data support the exploitation of IL-1 activity in the context of T cell vaccination strategies and warrant consideration of the impact of clinical IL-1 inhibition on the rollout of T cell immunity. Full article

(This article belongs to the Special Issue Cytokines in Inflammatory Signaling)

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