MyD88-Syk axis is a critical determinant for inflammatory response in macrophages

2019 ◽  
Author(s):  
Young-Su Yi ◽  
Ji Hye Kim ◽  
Woo Seok Yang ◽  
Eunji Kim ◽  
Deok Jeong ◽  
...  
Keyword(s):  
Phagocytic Activity ◽  
Inflammatory Responses ◽  
Kinase Domain ◽  
Raw264.7 Cells ◽  
Cytokine Signaling ◽  
Filamentous Actin ◽  
Suppressor Of Cytokine Signaling ◽  
Nf Kappa B ◽  
Critical Determinant ◽  
Activation Motif

Inhibition of Syk or MyD88 decreased generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and consequent ROS/RNS-induced phagocytic activity in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Syk inhibition downregulated expression of ROS/RNS-generating enzymes by inhibiting the nuclear factor-kappa B (NF-kappa?B) signaling pathway and phagocytic activity by suppressing suppressor of cytokine signaling 1 (SOCS1) via its nitration in the LPS-stimulated RAW264.7 cells. Inhibition of ROS/RNS generation suppressed SOCS1 nitration, leading to a decrease in the phagocytic activity. Syk was activated by the interaction with MyD88, and the tyrosine 58 residue (Y58) in the hemi-immunoreceptor tyrosine-based activation motif (ITAM) of MyD88 was critical for interaction and consequent activation of Syk in macrophages. Src activated MyD88 by phosphorylation at Y58 via the Src kinase domain. Moreover, LPS-induced formation of filamentous actin (F-actin) and Ras-related C3 botulinum toxin substrate 1 (Rac1) activation induced Src activation. Conclusivley, these results suggest that the MyD88-Syk axis plays a pivotal role in macrophage-mediated inflammatory responses by inducing ROS/RNS generation and phagocytic activity via activation of Src and its upstream stimulators, F-actin and Rac1.

scholarly journals Syk-MyD88 Axis Is a Critical Determinant of Inflammatory-Response in Activated Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Young-Su Yi ◽  
Han Gyung Kim ◽  
Ji Hye Kim ◽  
Woo Seok Yang ◽  
Eunji Kim ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Src Kinase ◽  
Kinase Domain ◽  
Primary Response ◽  
Raw264.7 Cells ◽  
Filamentous Actin ◽  
Critical Determinant ◽  
Mutation Strategy ◽  
Underlying Mechanisms

BackgroundInflammation, a vital immune response to infection and injury, is mediated by macrophage activation. While spleen tyrosine kinase (Syk) and myeloid differentiation primary response 88 (MyD88) are reportedly involved in inflammatory responses in macrophages, their roles and underlying mechanisms are largely unknown.MethodsHere, the role of the MyD88-Syk axis and the mechanism by which Syk and MyD88 cooperate during macrophage-mediated inflammatory responses are explored using knockout conditions of these proteins and mutation strategy as well as flowcytometric and immunoblotting analyses.ResultsSyk rapidly activates the nuclear factor-kappa B (NF-κB) signaling pathway in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and the activation of the NF-κB signaling pathway is abolished in Syk−/− RAW264.7 cells. MyD88 activates Syk and Syk-induced activation of NF-κB signaling pathway in LPS-stimulated RAW264.7 cells but Syk-induced inflammatory responses are significantly inhibited in MyD88−/− RAW264.7 cells. MyD88 interacts with Syk through the tyrosine 58 residue (Y58) in the hemi-immunoreceptor tyrosine-based activation motif (ITAM) of MyD88, leading to Syk activation and Syk-induced activation of the NF-κB signaling pathway. Src activates MyD88 by phosphorylation at Y58 via the Src kinase domain. In addition, Ras-related C3 botulinum toxin substrate 1 (Rac1) activation and Rac1-induced formation of filamentous actin (F actin) activate Src in LPS-stimulated RAW264.7 cells.ConclusionsThese results suggest that the MyD88-Syk axis is a critical player in macrophage-mediated inflammatory responses, and its function is promoted by an upstream Src kinase activated by Rac1-generated filamentous actin (F-actin).

scholarly journals Immune-to-brain signaling and central prostaglandin E2 synthesis in fasted rats with altered lipopolysaccharide-induced fever

2008 ◽  
Vol 295 (1) ◽  
pp. R133-R143 ◽  
Author(s):  
Wataru Inoue ◽  
Gokce Somay ◽  
Stephen Poole ◽  
Giamal N. Luheshi
Keyword(s):  
Inflammatory Responses ◽  
Mammalian Species ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Plasma Cytokines ◽  
Thermoregulatory Function ◽  
Underlying Mechanisms ◽  
Fever Response ◽  
The Brain ◽  
Fasted Rats

Acute starvation attenuates the fever response to pathogens in several mammalian species. The underlying mechanisms responsible for this effect are not fully understood but may involve a compromised immune and/or thermoregulatory function, both of which are prerequisites for fever generation. In the present study, we addressed whether the impaired innate immune response contributes to the reported attenuation of the fever response in fasted rats during LPS-induced inflammation. Animals fasted for 48 h exhibited a significant and progressive hypothermia prior to drug treatment. An intraperitoneal injection of LPS (100 μg/kg) resulted in a significantly attenuated fever in the fasted animals compared with the fed counterparts. This attenuation was accompanied by the diminution in the concentration of some [TNF and IL-1 receptor antagonist (RA)] but not all (IL-1β and IL-6) of the plasma cytokines normally elevated in association with the fever response. Nevertheless, fasting had no effect on the LPS-induced inflammatory responses at the level of the brain, as assessed by mRNA expressions of inhibitory factor(I)-κB, suppressor of cytokine signaling (SOCS3), IL-1β, cyclooxygenase (COX)-2, and microsomal PGE synthase (mPGES)-1 in the hypothalamus, as well as by PGE2 elevations in the cerebrospinal fluid. In contrast, fasting significantly attenuated the fever response to central PGE2 injection. These results show that fasting does not alter the febrigenic signaling from the periphery to the brain important for central PGE2 synthesis but does affect thermoregulatory mechanisms downstream of and/or independent of central PGE2 action.

scholarly journals Impaired IFN-γ-Dependent Inflammatory Responses in Human Keratinocytes Overexpressing the Suppressor of Cytokine Signaling 1

2002 ◽  
Vol 169 (1) ◽  
pp. 434-442 ◽  
Author(s):  
Monica Federici ◽  
Maria Laura Giustizieri ◽  
Claudia Scarponi ◽  
Giampiero Girolomoni ◽  
Cristina Albanesi
Keyword(s):  
Inflammatory Responses ◽  
Human Keratinocytes ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Ifn Γ

Depletion of suppressor of cytokine signaling-1a causes hepatic steatosis and insulin resistance in zebrafish

2015 ◽  
Vol 308 (10) ◽  
pp. E849-E859 ◽  
Author(s):  
Ziru Dai ◽  
Hualin Wang ◽  
Xia Jin ◽  
Houpeng Wang ◽  
Jiangyan He ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Hepatic Steatosis ◽  
Inflammatory Responses ◽  
Somatic Growth ◽  
Normal Growth ◽  
Cytokine Signaling ◽  
Adult Zebrafish ◽  
Transcription Activator ◽  
Suppressor Of Cytokine Signaling ◽  
Terrestrial Mammals

Suppressor of cytokine signaling-1a (SOCS1a) is a member of the suppressor of cytokine signaling family, a group of related molecules that mediate the negative regulation of the JAK-STAT pathway. Here, we depleted SOCS1a using the transcription activator-like (TAL) effector nuclease (TALEN) technique to understand its physiological roles in zebrafish. Although elevated levels of JAK-STAT5 activation and erythropoiesis have been observed in socs1a-deficient zebrafish, these animals exhibited normal growth during the early stages. Socs1a-deficient zebrafish began to grow slowly with certain mortalities after 20 days postfertilization (dpf), whereas the heterozygous socs1a-deficient zebrafish exhibited enhanced somatic growth. Decreased adiposity, hepatic steatosis, and insulin resistance were observed in our socs1a-deficient adult zebrafish, which is similar to the lipodystrophy phenotypes observed in mammals. Comparative transcriptomic analyses revealed elevated levels of gluconeogenesis, lipolysis, and hypoxia-inducible response and decreased activities of lipogenesis and glycolysis in the hepatocytes of socs1a-deflicient adult zebrafish. Evident mitochondrial dysfunction has also been observed in hepatocytes from socs1a-deficient zebrafish. Taken together, our results suggest that the negative regulatory roles of SOCS1a on JAK-STAT5 signaling may be involved in the suppression of the erythropoiesis and growth hormone activities, which was also reflected in the enhanced somatic growth performance observed in the heterozygous socs1a-deficient fish. The differences in the effects caused by SOCS1a depletion on insulin sensitivity, lipid metabolism, and inflammatory responses between zebrafish and mammalian models observed here may reflect differences between the functional mechanisms of SOCS members in terrestrial mammals and aquatic teleosts.

Die Aktivierung der MKK6/p38 Kaskade ist essentiell für die Stabilisierung der Suppressor of Cytokine Signaling 3 mRNA durch TNF-alpha

2006 ◽  
Vol 44 (01) ◽  
Author(s):  
C Ehlting ◽  
F Schaper ◽  
ED Brenndörfer ◽  
PC Heinrich ◽  
D Häussinger ◽  
...  
Keyword(s):  
Tnf Alpha ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling
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