Interleukin 24 (IL-24) is a member of the IL-10 cytokine family and is primarily synthesized by lymphocytes and activated monocytes. IL-24 exerts its immunological functions by interacting with membrane receptors or intracellular proteins, leading to the activation of Janus protein tyrosine kinase/signal transducer and activator of transcription (JAK/STAT), p38 mitogen-activated protein kinase (p38 MAPK), and endoplasmic reticulum stress pathways in target cells. This versatile cytokine has specific abilities to inhibit tumor proliferation and invasion, expedite wound healing, and contribute to cardiovascular protection. IL-24 is involved in the pathogenesis of various autoimmune and inflammatory disorders, presenting itself as a prospective therapeutic target for the treatment of such conditions. This article primarily delves into the role and mechanisms of IL-24 in physiological processes, aiming to provide novel insights and avenues for disease treatment.
Humans ; Animals ; Interleukins/physiology* ; Signal Transduction ; Endoplasmic Reticulum Stress ; p38 Mitogen-Activated Protein Kinases/metabolism* ; Neoplasms/metabolism* ; Autoimmune Diseases/metabolism* ; Inflammation/immunology* ; STAT Transcription Factors/metabolism* ; Janus Kinases/metabolism*

OBJECTIVETo investigate the levels of cytokines related to T-helper (Th) 17 cells in serum and signal transducers in the psoriatic lesions of patients with psoriasis vulgaris of blood-heat syndrome (BHS) and blood-stasis syndrome (BSS).

METHODSSixty patients with psoriasis vulgaris were divided into the BHS and BSS groups according to the syndrome differentiation of Chinese medicine (CM). Ten healthy subjects were considered as the control group. Cytokine levels of interleukin (IL)-17, IL-23 and IL-6 in serum were determined by enzyme-linked immunosorbent assay. Expression levels of signal transducer and activator of transcription 3 (STAT3), p38-mitogen-activated protein kinase (MAPK) and STAT6 in the psoriatic lesions were determined using immunohistochemistry (IHC), Western blot, and real-time quantitative reverse transcription polymerase chain reaction, respectively.

RESULTSProduction of IL-17, IL-23 and IL-6 in the BHS group and BSS group were significantly increased compared with those in the control group (P<0.05). Levels of IL-17 and IL-23 in the BHS group were higher than those in the BSS group (P<0.05). Compared with the control group, IHC positive expressions and protein expressions of STAT3 and p38-MAPK, and the STAT3 mRNA expressions in the BHS and BSS groups were significantly higher (P<0.05 or P<0.01). The protein expression of STAT3 in the BHS group was significantly higher than that in the BSS group (P<0.05).

CONCLUSIONSCytokines in serum and signal transducers in the psoriatic lesions alter with various CM syndromes of psoriasis. The results provide scientific basis for the treatment based on syndrome differentiation of CM in treating psoriasis vulgaris.

Adult ; Female ; Gene Expression Regulation ; Humans ; Immunohistochemistry ; Interleukin-17 ; blood ; Interleukin-23 ; blood ; Interleukin-6 ; blood ; Male ; Psoriasis ; blood ; enzymology ; genetics ; immunology ; RNA, Messenger ; genetics ; metabolism ; STAT3 Transcription Factor ; genetics ; metabolism ; STAT6 Transcription Factor ; genetics ; metabolism ; Signal Transduction ; Syndrome ; Th17 Cells ; immunology ; p38 Mitogen-Activated Protein Kinases ; genetics ; metabolism

OBJECTIVETo investigate the effects of sapindus saponins on myocardial inflammation mediated by Ang II/ p38MAPK signal pathway and cardiac hypertrophy in spontaneously hypertensive rats. And also to explore the correlation of cardiac hypertrophy and inflammation.

METHODThirty-two 16-week-old spontaneously hypertensive rats (SHR) were randomly divided into four groups, one with placebo as model group, one with captopril tablets (27 mg x kg(-1)) as positive control, one with low-dose sapindus saponins (27 mg x kg(-1)), one with high-dose (108 mg x kg(-1)). And another eight healthy Wistar-Kyoto strain (WKY) rats were used as the normal group. The animals were treated for eight weeks, and the indicators detected were as follows: (1) left ventricular mass index (LVMI); (2) the content of Ang II and hs-CRP in plasma were determined by ELISA; (3) the protein expression of AT1R and VEGF were determined by immunohistochemical method; (4) the protein expression of p-p38MAPK in myocardial cells was determined by Western blot.

RESULTSapindus saponins reduced LVMI, and blocked the expression level of Ang II, AT1R, p-p38MAPK, VEGF and hs-CRP in myocardial tissue. Vs the SHR model group, there were significant differences (P < 0.05 or P < 0.01).

CONCLUSIONOur findings suggested that sapindus saponins could inhibited cardiac hypertrophy, the possible mechanisms may be related to the inhibition on inflammatory response mediated by Ang II/p38MAPK pathway.

Angiotensin II ; immunology ; Animals ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Hypertension ; complications ; drug therapy ; immunology ; Hypertrophy, Left Ventricular ; drug therapy ; etiology ; immunology ; Male ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Rats, Wistar ; Sapindus ; chemistry ; Saponins ; administration & dosage ; p38 Mitogen-Activated Protein Kinases ; immunology

The p38 mitogen-activated protein kinase (MAPK) plays an evolutionarily conserved role in the cellular response to microbial infection and environmental stress. Activation of p38 is mediated through phosphorylation by upstream MAPKK, which in turn is activated by MAPKKK. In the Caenorhabditis elegans, the p38 MAPK (also called PMK-1) signaling pathway has been shown to be required in its resistance to bacterial infection. However, how different upstream MAP2Ks and MAP3Ks specifically contribute to the activation of PMK-1 in response to bacterial infection still is not clearly understood. By using double-stranded RNA-mediated interference (RNAi) and genetic mutants of C. elegans, we demonstrate that C. elegans MOM-4, a mammalian TAK1 homolog, is required for the resistance of C. elegans to a P. aeruginosa infection. We have also found that the MKK-4 of C. elegans is required for P. aeruginosa resistance, but not through the regulation of DLK-1. In summary, our results indicate that different upstream MAPKKKs or MAPKKs regulate the activation of PMK-1 in response to P. Aeruginosa.
Animals ; Caenorhabditis elegans ; enzymology ; genetics ; immunology ; microbiology ; Caenorhabditis elegans Proteins ; genetics ; metabolism ; Disease Resistance ; Enzyme Activation ; MAP Kinase Kinase 1 ; metabolism ; MAP Kinase Signaling System ; Membrane Proteins ; deficiency ; genetics ; metabolism ; Mutation ; Pseudomonas Infections ; enzymology ; Pseudomonas aeruginosa ; physiology ; RNA Interference ; p38 Mitogen-Activated Protein Kinases ; metabolism

OBJECTIVETo observe the effect of andrographolide on the activation of mitogen-activated protein kinases (MAPKs) and expression of nuclear factor-κB (NF-κB) in macrophage foam cells.

METHODSThe mouse peritoneal macrophages were cultured in the media in the presence of oxidized low-density lipoprotein (ox-LDL), ox-LDL+andrographolide, or neither (control). The phosphorylation of MAPK molecules (p38MAPK, JNK, ERK1/2) and the expressions of NK-κB p65 were examined by Western blot.

RESULTSAs compared with cells in the control group, the expressions of phospho-p38 and NF-κB p65 were increased in the cells cultured with either ox-LDL or ox-LDL+andrographolide (P<0.01), but attenuated significantly in the presence of ox-LDL+ andrographolide when compared with ox-LDL (P<0.05). The phospho-JNK increased in the presence of either ox-LDL or ox-LDL+andrographolide when compared with control cells (P<0.01), but no significant difference existed between ox-LDL and ox-LDL+andrographolide (P>0.05). The expression of phospho-ERK1/2 was increased in the presence of ox-LDL compared with the control cells (P<0.01), but no significant differences existed between the cells cultured in the presence of ox-LDL+andrographolide and the control medium (P>0.05).

CONCLUSIONSAndrographolide could inhibit the activation of ERK1/2, p38MAPK and NK-κB induced by ox-LDL in macrophage foam cells, which might be one of its mechanisms in preventing atherosclerosis.

Animals ; Anti-Inflammatory Agents ; pharmacology ; Atherosclerosis ; immunology ; metabolism ; prevention & control ; Cells, Cultured ; Diterpenes ; pharmacology ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Foam Cells ; cytology ; drug effects ; enzymology ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Lipoproteins, LDL ; metabolism ; MAP Kinase Signaling System ; drug effects ; immunology ; Macrophages, Peritoneal ; cytology ; drug effects ; enzymology ; Mice ; Mice, Inbred Strains ; NF-kappa B ; metabolism ; Vasculitis ; drug therapy ; immunology ; metabolism ; p38 Mitogen-Activated Protein Kinases ; metabolism

This study is to investigate the anti-allergic effect of anthocyanidin and to explore its possible mechanism. The experiments of passive cutaneous anaphylaxis reaction (PCA) and colorimetry were used to determine the effect of anthocyanidin on degranulation of mast cells in vivo. For in vitro study, various concentrations of anthocyanidin (100, 50 and 25 micromol x L(-1)) were added to the culture medium of mast cells cultured with 100 microg x L(-1) of dinitrophenyl (DNP) specific IgE overnight. The azelastine (100 micromol x L(-1)) was selected as the positive control. The antigen (DNP-human serum albumin, DNP-HAS)-induced release of degranulation was measured by enzymatic assay, histamine was determined by EIA, and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured by Western blotting, separately. In addition, the effects of anthocyanidin on phosphorylation of NF-kappaB, p38MAPK and Akt were observed by Western blotting. The results showed that treatments with anthocyanidin (100 and 50 mg x kg(-1)) were followed by a decrease in PCA of rats. Anthocyanidin (100 and 50 micromol x L(-1)) obviously suppressed the degranulation from mast cells, whereas results from anthocyanidin (100 and 50 micromol x L(-1)) group indicated significant inhibitory effect on histamine, the calcium uptake, TNF-alpha, IL-6, phosphorylation of NF-kappaB, p38MAPK and Akt of mast cells induced by antigen. Anthocyanidin may suppress the anaphylactic reaction by inhibiting the action of mast cells. NF-kappaB, p38MAPK and Akt at least in part contribute to this event.
Animals ; Anthocyanins ; pharmacology ; Anti-Allergic Agents ; pharmacology ; Calcium ; metabolism ; Cell Degranulation ; drug effects ; Histamine Release ; drug effects ; Immunoglobulin E ; immunology ; Interleukin-6 ; metabolism ; Male ; Mast Cells ; immunology ; metabolism ; physiology ; Passive Cutaneous Anaphylaxis ; drug effects ; Proto-Oncogene Proteins c-akt ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Transcription Factor RelA ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism ; p38 Mitogen-Activated Protein Kinases ; metabolism

OBJECTIVETo explore the protective effects and mechanism of ethanol extract of Inonotus obliquus (EEIO) injection on asthmatic mice.

METHODOVA was injected intraperitoneally and inhaled to produce the asthmatic model. Thirty two mice were randomly divided into four groups: control group, asthma group and I. obliquus groups of high and low dose. The concentrations of IL-4, IL-5, IL-13 and IFN-gamma in BALF, the phosphor-p38 MAPK in lung tissues were respectively measured by ELISA and Western blotting. The number of inflammatory cells in BALF and histopathology changes were observed.

RESULTIn asthmatic group, the number of inflammatory cells and the concentrations of IL-4, IL-5, IL-13 in BALF and phospho-p38 MAPK in lung tissue were higher, while IFN-gamma were lower than those in normal control mice (P < 0.05). In I. obliquus group, the number of inflammatory cells, the concentrations of IL-4, IL-5, IL-13 in BALF and phosphor-p38 MAPK in lung tissue were lower, but were higher than those in normal control mice (P < 0.05), and histropathology damage was alleviated significantly. There was no significant difference observed among the efficacies in the I. obliquus groups of high and low dose.

CONCLUSIONp38 MAPK may play a role in pathological process of asthma. I. obliquus effectively treats asthma by inhibiting the expression of phosphor-p38 MAPK, correcting the unbalance of IFN-gamma/IL-4 and decreasing the number of inflammatory cells.

Animals ; Anti-Asthmatic Agents ; isolation & purification ; pharmacology ; Asthma ; drug therapy ; metabolism ; pathology ; Basidiomycota ; chemistry ; Basophils ; drug effects ; metabolism ; Bronchoalveolar Lavage Fluid ; cytology ; immunology ; Disease Models, Animal ; Interferon-gamma ; drug effects ; metabolism ; Interleukin-13 ; metabolism ; Interleukin-4 ; metabolism ; Interleukin-5 ; metabolism ; Lung ; pathology ; Lymphocytes ; drug effects ; metabolism ; Mice ; Mice, Inbred BALB C ; Neutrophils ; drug effects ; metabolism ; Phytotherapy ; Plant Extracts ; pharmacology ; p38 Mitogen-Activated Protein Kinases ; drug effects ; metabolism

Cyclooxygenase-2 (COX-2) is an important enzyme in inflammation. In this study, we investigated the underlying molecular mechanism of the synergistic effect of rottlerin on interleukin1beta (IL-1beta)-induced COX-2 expression in MDA-MB-231 human breast cancer cell line. Treatment with rottlerin enhanced IL-1beta-induced COX-2 expression at both the protein and mRNA levels. Combined treatment with rottlerin and IL-1beta significantly induced COX-2 expression, at least in part, through the enhancement of COX-2 mRNA stability. In addition, rottlerin and IL-1beta treatment drove sustained activation of p38 Mitogen-activated protein kinase (MAPK), which is involved in induced COX-2 expression. Also, a pharmacological inhibitor of p38 MAPK (SB 203580) and transient transfection with inactive p38 MAPK inhibited rottlerin and IL-1beta-induced COX-2 upregulation. However, suppression of protein kinase C delta (PKC delta) expression by siRNA or overexpression of dominant-negative PKC delta (DN-PKC-delta) did not abrogate the rottlerin plus IL-1beta-induced COX-2 expression. Furthermore, rottlerin also enhanced tumor necrosis factor-alpha (TNF-alpha), phorbol myristate acetate (PMA), and lipopolysaccharide (LPS)-induced COX-2 expression. Taken together, our results suggest that rottlerin causes IL-1beta-induced COX-2 upregulation through sustained p38 MAPK activation in MDA-MB-231 human breast cancer cells.
Acetophenones/*pharmacology ; Benzopyrans/*pharmacology ; Breast Neoplasms/drug therapy/*genetics/immunology ; Cell Line, Tumor ; Cyclooxygenase 2/*genetics ; Enzyme Activation/drug effects ; Enzyme Inhibitors/*pharmacology ; Female ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Interleukin-1beta/*immunology ; MAP Kinase Signaling System/drug effects ; Mallotus Plant/chemistry ; NF-kappa B/immunology ; Protein Kinase C-delta/antagonists & inhibitors ; Reactive Oxygen Species/immunology ; p38 Mitogen-Activated Protein Kinases/*immunology

Previously, we reported that CD40-induced production of reactive oxygen species (ROS) by NADPH oxidase requires the TNF receptor-associated factor (TRAF) 3, as well as the activities of phosphatidylinositol 3-kinase (PI3K) and Rac1. Here we investigated the possible mechanisms of the production of ROS after CD40 ligation in B cells. We describe an alternative ROS production pathway that is triggered by CD40 ligation, involves 5-lipoxygenase (5-LO), and results in activation of p38 MAPK. Our studies in Raji human B lymphomas revealed that CD40-induced ROS production by 5-LO also requires the activities of PI3K and Rac1. In contrast to the NADPH oxidase pathway, however, TRAF molecules are not required for the CD40-induced ROS production by 5-LO. The association of CD40 with 5-LO is dependent on CD40 ligation in Raji B cells, and co-immunoprecipitation experiments using epitope-tagged proteins transiently expressed in human embryonic kidney 293T cells revealed the role of the regulatory subunit of PI3K, p85, in this association. Collectively, these data suggest a separate pathway for the CD40-induced ROS production in B cells and demonstrate that this pathway requires 5-LO via direct association of p85 with both CD40 and 5-LO.
Antigens, CD40/*metabolism ; Arachidonate 5-Lipoxygenase/*metabolism ; B-Lymphocytes/*enzymology/immunology ; CD40 Ligand/metabolism ; Cell Line, Tumor ; *Enzyme Activation ; HEK293 Cells ; Humans ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Binding ; *Reactive Oxygen Species/metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/*metabolism ; rac GTP-Binding Proteins/metabolism

OBJECTIVEDifferent from primary membranous nephropathy, hepatitis B virus associated membranous nephropathy (HBV-MN) shows lower deposits of membrane attack complex (C5b-9) in glomerular subepithelium. The causes of relatively low complement activation in this disease remain unclear. The aim of this study was to investigate the influence of hepatitis B x protein (HBx) on the expression of CD59 and Crry in mouse podocytes.

METHODCultured mouse podocytes were divided into adenovirus vector hepatitis B virus X gene (Ad-HBx) transfected group (Ad-X group), blank podocytes group (B group) and adenovirus vector transfected group (Ad group). CD59 and Crry mRNA expression were assayed by semiquantitative RT-PCR. CD59 and Crry expression were tested by flow cytometry. The effect of HBx on complement activation was evaluated with MTT method. And then, the effects of P38MAPK, PI-3K and ERK1/2 pathway inhibitors (SB203580, LY294002, U0126) and DMSO on CD59 and Crry expression were respectively detected by flow cytometry.

RESULTProteins CD59 and Crry expression rates (%) in group B, Ad group and Ad-X group were 17.71 ± 3.81, 18.29 ± 3.36 and 45.7 ± 9.01; 18 ± 2.31, 21.78 ± 2.01 and 47.45 ± 9.95, respectively. Compared with group B, CD59 and Crry expression in group Ad was not significantly different (P values for both > 0.05), but CD59 and Crry protein expression in Ad-X group was significantly higher than that in groups B and Ad (P values for both < 0.005); CD59 and Crry gene expression in group Ad was not significantly different from that in group B (P values for both > 0.05). However, CD59 and Crry gene expression of Ad-X group was significantly higher than that in groups B and Ad (P values for both < 0.05). Flow cytometry detected CD59 protein expression rates (%) were 17.35 ± 1.24, 46.19 ± 9.77, 43.03 ± 6.83 and 40.04 ± 6.39 and Crry protein expression rates (%) were 18.14 ± 3.56, 31.95 ± 1.68, 31.95 ± 1.69 and 37.14 ± 3.92 after SB203580, LY294002, U0126 and DMSO were added to Ad-X group respectively. P38 pathway inhibition resulted in significantly lower CD59 and Crry expression than Ad-X group (P values for all < 0.005), but PI-3K, ERK1/2 pathway inhibitors and DMSO had no significant effect on the expression of CD59 and Crry (P values for all > 0.05). The inhibition rates of cell lysis were significantly higher in Ad-X group than in groups B and Ad at each serum dilution point (P values for all < 0.05), while groups B and Ad had no significant difference in cell viability.

CONCLUSIONHBx can up-regulate CD59 and Crry expression in podocytes through activating P38 pathway, resulting in decreased complement activation, which may facilitate latent HBV infection in podocytes and play a role in development of hepatitis B virus associated glomerulonephritis (HBV-GN).

Animals ; CD59 Antigens ; metabolism ; Cells, Cultured ; Mice ; Podocytes ; immunology ; metabolism ; Receptors, Complement ; metabolism ; Trans-Activators ; metabolism ; p38 Mitogen-Activated Protein Kinases ; metabolism