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Cytokines Stimulated by IL-33 in Human Skin Mast Cells: Involvement of NF-κB and p38 at Distinct Levels and Potent Co-Operation with FcεRI and MRGPRX2
- Source :
- International Journal of Molecular Sciences, Volume 22, Issue 7, International Journal of Molecular Sciences, Vol 22, Iss 3580, p 3580 (2021)
- Publication Year :
- 2021
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2021.
-
Abstract
- The IL-1 family cytokine IL-33 activates and re-shapes mast cells (MCs), but whether and by what mechanisms it elicits cytokines in MCs from human skin remains poorly understood. The current study found that IL-33 activates CCL1, CCL2, IL-5, IL-8, IL-13, and TNF-α, while IL-1β, IL-6, IL-31, and VEGFA remain unaffected in cutaneous MCs, highlighting that each MC subset responds to IL-33 with a unique cytokine profile. Mechanistically, IL-33 induced the rapid (1–2 min) and durable (2 h) phosphorylation of p38, whereas the phosphorylation of JNK was weaker and more transient. Moreover, the NF-κB pathway was potently activated, as revealed by IκB degradation, increased nuclear abundance of p50/p65, and vigorous phosphorylation of p65. The activation of NF-κB occurred independently of p38 or JNK. The induced transcription of the cytokines selected for further study (CCL1, CCL2, IL-8, TNF-α) was abolished by interference with NF-κB, while p38/JNK had only some cytokine-selective effects. Surprisingly, at the level of the secreted protein products, p38 was nearly as effective as NF-κB for all entities, suggesting post-transcriptional involvement. IL-33 did not only instruct skin MCs to produce selected cytokines, but it also efficiently co-operated with the allergic and pseudo-allergic/neurogenic activation networks in the production of IL-8, TNF-α, CCL1, and CCL2. Synergism was more pronounced at the protein than at the mRNA level and appeared stronger for MRGPRX2 ligands than for FcεRI. Our results underscore the pro-inflammatory nature of an acute IL-33 stimulus and imply that especially in combination with allergens or MRGPRX2 agonists, IL-33 will efficiently amplify skin inflammation and thereby aggravate inflammatory dermatoses.
- Subjects :
- Male
Receptors, Neuropeptide
medicine.medical_treatment
FcεRI
mast cells
p38 Mitogen-Activated Protein Kinases
NF-κB
Receptors, G-Protein-Coupled
lcsh:Chemistry
chemistry.chemical_compound
Phosphorylation
lcsh:QH301-705.5
Spectroscopy
Chemistry
General Medicine
Computer Science Applications
Cell biology
Cytokine
MRGPRX2
medicine.symptom
signaling
Signal Transduction
skin
p38 mitogen-activated protein kinases
Foreskin
Primary Cell Culture
Nerve Tissue Proteins
Inflammation
p38
CCL1
CCL2
Article
Catalysis
Inorganic Chemistry
synergism
medicine
Humans
Physical and Theoretical Chemistry
Molecular Biology
Receptors, IgE
Organic Chemistry
JNK Mitogen-Activated Protein Kinases
Interleukin-33
cytokines
Interleukin 33
lcsh:Biology (General)
lcsh:QD1-999
IL-33
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....3191840bd021d4dac2bc8bacd9478b14
- Full Text :
- https://doi.org/10.3390/ijms22073580