Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy

Cytokine and glucocorticoid (GC) hormone signaling act in an integrated fashion to control inflammation and immune response. Here we establish a new mode of interaction of these two pathways and propose Suppressor of Cytokine Signaling (SOCS)-1 as an essential player in mediating cross-talk. We observed that glucocorticoid receptor (GR) and SOCS1 form an intracellular complex through an interaction, which required the SH2 domain of SOCS1 and the ligand binding domain of GR. Furthermore, GC stimulation was found to increase the nuclear level of SOCS1. SOCS1 binding to the GR did not require ligand binding of the receptor; however, it was abolished after long term GC stimulation, suggesting a functional role of the interaction for the early phase of GC action. The interaction between GR and SOCS1 appeared to negatively influence the transcription of the two GR-regulated genes, FKBP5 and MKP1, because the GC-dependent expression of these genes was inhibited by the SOCS1 inducer IFN␥ and enhanced in SOCS1-deficient murine embryonic fibroblasts as compared with IFN␥ treated wild-type cells. Our results suggest a prominent role of SOCS1 in the early phase of cross-talk between GR and cytokine signaling.Key principles determining the cellular response to cytokine signaling are duration of stimulus, prevalence of inhibitory feedback mechanisms, and operation of cross-talk with other cellular pathways. All of these factors interact to influence the strength and the quality of the physiological response. For cytokines operating via the Janus kinase (JAK) 2 /signal transducers and activators of transcription (STAT) pathway, both suppressor of cytokine signaling (SOCS) proteins and the glucocorticoid receptor (GR) have been identified as important intracellular regulators in this respect.SOCS proteins have been shown to serve both as feedback inhibitors as well as mediators of cross-talk with other signaling pathways. They comprise a family of 8 members, initially described as negative feedback regulators of the JAK/STAT pathway. All SOCS proteins share two functional domains: an SH2 domain, which primarily enables binding of phosphorylated tyrosine residues, and a C-terminal SOCS box, which serves as a recruiting site for ubiquitin ligases, thereby combining specific inhibition of JAK catalytic activity with generic mechanisms such as competition over binding sites and targeting of associated proteins to proteasomal degradation (1, 2).Recent evidence suggests that the negative regulatory function of SOCS is not restricted to the JAK/STAT pathway. Through interaction with other signaling intermediates SOCS proteins can interfere with crucial signaling pathways such as the NF-B and insulin receptor signaling pathways (3). Furthermore glucocorticoids (GC) can also influence cytokine signaling. They act together with cytokines in an integrated fashion to control inflammation, immune response, and other more diverse physiological functions in mammals (4). The effect of GCs is mediated by the GR, a member of the nuclear receptor...

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“…Murine BMDM were prepared as described recently (9). All cells were cultivated in 5% CO 2 at 37°C and subcultured every 3-4 days.…”

Section: Methodsmentioning

confidence: 99%

Interaction and Functional Interference of Glucocorticoid Receptor and SOCS1

Haffner

Jurgeit

Berlato

et al. 2008

Journal of Biological Chemistry

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“…However, when the analysis of GR dim mice was expanded to other inflammatory processes, we observed a failure of GCs to exert a full anti-inflammatory response. This was the case for exogenous actions of GCs in contact allergy and for the modulatory role of endogenous GCs in septic shock and for the early response during wound healing exhibiting elevated cytokine and chemokine expression (Grose et al, 2002;Tuckermann et al, 2007). As a side effect GC inhibition of bone formation occur in these mice.…”

Section: Resultsmentioning

confidence: 99%

“…From the croton oil experiments one could conclude that dimerized-induced DNA binding can be omitted for suppression of inflammatory skin diseases. However, recent studies in contact hypersensitivity, a model for contact dermatitis and thus an inflammatory type of a different mechanism revealed that more than transrepression of the GR is required for suppression of inflammation (Tuckermann et al, 2007). This has consequences for therapeutic strategies, for example one would expect that function selective GR ligands (SEGRAs) that address the transrepression activity with the hope to reduce atrophy of the skin (Schoepe et al, 2006) would be potent in the treatment of irritant dermatitis, but less in contact allergy.…”

Section: Exogenous Gc Action In Skin Inflammationmentioning

confidence: 99%

“…Phenotype Beneficial Effects of GC Treatment of irritant dermatitis like in wild type (Reichardt et al, 2001) Treatment of CHS impaired (Tuckermann et al, 2007) Suppression of inflammatory mediators like in wild type: TNFa (Tuckermann et al, 2007), MMP-13, MMP-9 (Tuckermann et al, 1999) impaired : MCP-1, IP-10, IL-1b (Grose et al, 2002;Tuckermann et al, 2007) PI3K coactivation by high dose GC, important for stero id protection from stroke like in wild type: PI3K activity normal in GR dim MEFs (Limbourg et al, 2002) …”

Section: Phenotypes Of Pharmacological Gc Administration In Gr Dim Micementioning

confidence: 99%

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Glucocorticoid receptor action in beneficial and side effects of steroid therapy: Lessons from conditional knockout mice

Kleiman

Tuckermann

2007

Molecular and Cellular Endocrinology

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145

122

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Tuckermann. Glucocorticoid receptor action in beneficial and side effects of steroid therapy: Lessons from conditional knockout mice. Molecular and Cellular Endocrinology, Elsevier, 2007, 275 (1-2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. dimerization-deficient GR demonstrate that some inflammatory processes can be suppressed by GCs, while others can not. Also side effects of GCs occur in these mice. Thus, depending on the process that is treated, SEGRA could be therapeutically more or less effective and not all side effects of steroid therapy may be reduced.

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“…However, exposure of DCs to nickel sulfate stimulates signal transduction pathways and augments expression of MHC class II and several costimulatory molecules in different manners compared to that of DNFB (16). Macrophages are a subpopulation of cells in the mouse dermis that have gained attention as a useful therapeutic target for contact allergies (17)(18)(19). In a previous study, we examined macrophage inflammatory protein 2 (MIP-2) expression in topically DNFB-applied skin and the DNFB-treated RAW 264.7 cells (19).…”

Section: Introductionmentioning

confidence: 99%