Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN
Allergy is a chronic inflammatory disease, and its incidence has increased worldwide in recent years. Thalidomide, which was initially used as an anti-emetic drug but was withdrawn due to its teratogenic effects, is now used to treat blood cancers. Although the anti-inflammatory and immunomodulatory...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/12/3/469 |
| _version_ | 1797624914252922880 |
|---|---|
| author | Hyeun-Wook Chang Kyeong-Hwa Sim Youn-Ju Lee |
| author_facet | Hyeun-Wook Chang Kyeong-Hwa Sim Youn-Ju Lee |
| author_sort | Hyeun-Wook Chang |
| collection | DOAJ |
| description | Allergy is a chronic inflammatory disease, and its incidence has increased worldwide in recent years. Thalidomide, which was initially used as an anti-emetic drug but was withdrawn due to its teratogenic effects, is now used to treat blood cancers. Although the anti-inflammatory and immunomodulatory properties of thalidomide have been reported, little is known about its influence on the mast cell-mediated allergic reaction. In the present study, we aimed to evaluate the anti-allergic activity of thalidomide and the underlying mechanism using mouse bone marrow-derived mast cells (BMMCs) and passive cutaneous anaphylaxis (PCA) mouse models. Thalidomide markedly decreased the degranulation and release of lipid mediators and cytokines in IgE/Ag-stimulated BMMCs, with concurrent inhibition of FcεRI-mediated positive signaling pathways including Syk and activation of negative signaling pathways including AMP-activated protein kinase (AMPK) and SH2 tyrosine phosphatase-1 (SHP-1). The knockdown of AMPK or SHP-1 with specific siRNA diminished the inhibitory effects of thalidomide on BMMC activation. By contrast, the knockdown of cereblon (CRBN), which is the primary target protein of thalidomide, augmented the effects of thalidomide. Thalidomide reduced the interactions of CRBN with Syk and AMPK promoted by FcεRI crosslinking, thereby relieving the suppression of AMPK signaling and suppressing Syk signaling. Furthermore, oral thalidomide treatment suppressed the PCA reaction in mice. In conclusion, thalidomide suppresses FcεRI-mediated mast cell activation by activating the AMPK and SHP-1 pathways and antagonizing the action of CRBN, indicating that it is a potential anti-allergic agent. |
| first_indexed | 2024-03-11T09:49:23Z |
| format | Article |
| id | doaj.art-a835e2ff28e3483f9ab59a8cd16c8b2a |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T09:49:23Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-a835e2ff28e3483f9ab59a8cd16c8b2a2023-11-16T16:22:05ZengMDPI AGCells2073-44092023-02-0112346910.3390/cells12030469Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBNHyeun-Wook Chang0Kyeong-Hwa Sim1Youn-Ju Lee2College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of KoreaDepartment of Pharmacology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of KoreaDepartment of Pharmacology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of KoreaAllergy is a chronic inflammatory disease, and its incidence has increased worldwide in recent years. Thalidomide, which was initially used as an anti-emetic drug but was withdrawn due to its teratogenic effects, is now used to treat blood cancers. Although the anti-inflammatory and immunomodulatory properties of thalidomide have been reported, little is known about its influence on the mast cell-mediated allergic reaction. In the present study, we aimed to evaluate the anti-allergic activity of thalidomide and the underlying mechanism using mouse bone marrow-derived mast cells (BMMCs) and passive cutaneous anaphylaxis (PCA) mouse models. Thalidomide markedly decreased the degranulation and release of lipid mediators and cytokines in IgE/Ag-stimulated BMMCs, with concurrent inhibition of FcεRI-mediated positive signaling pathways including Syk and activation of negative signaling pathways including AMP-activated protein kinase (AMPK) and SH2 tyrosine phosphatase-1 (SHP-1). The knockdown of AMPK or SHP-1 with specific siRNA diminished the inhibitory effects of thalidomide on BMMC activation. By contrast, the knockdown of cereblon (CRBN), which is the primary target protein of thalidomide, augmented the effects of thalidomide. Thalidomide reduced the interactions of CRBN with Syk and AMPK promoted by FcεRI crosslinking, thereby relieving the suppression of AMPK signaling and suppressing Syk signaling. Furthermore, oral thalidomide treatment suppressed the PCA reaction in mice. In conclusion, thalidomide suppresses FcεRI-mediated mast cell activation by activating the AMPK and SHP-1 pathways and antagonizing the action of CRBN, indicating that it is a potential anti-allergic agent.https://www.mdpi.com/2073-4409/12/3/469thalidomidemast cellallergySrc homology 2 domain-containing phosphatase-1adenosine monophosphate-activated protein kinasecereblon |
| spellingShingle | Hyeun-Wook Chang Kyeong-Hwa Sim Youn-Ju Lee Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN Cells thalidomide mast cell allergy Src homology 2 domain-containing phosphatase-1 adenosine monophosphate-activated protein kinase cereblon |
| title | Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN |
| title_full | Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN |
| title_fullStr | Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN |
| title_full_unstemmed | Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN |
| title_short | Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN |
| title_sort | thalidomide attenuates mast cell activation by upregulating shp 1 signaling and interfering with the action of crbn |
| topic | thalidomide mast cell allergy Src homology 2 domain-containing phosphatase-1 adenosine monophosphate-activated protein kinase cereblon |
| url | https://www.mdpi.com/2073-4409/12/3/469 |
| work_keys_str_mv | AT hyeunwookchang thalidomideattenuatesmastcellactivationbyupregulatingshp1signalingandinterferingwiththeactionofcrbn AT kyeonghwasim thalidomideattenuatesmastcellactivationbyupregulatingshp1signalingandinterferingwiththeactionofcrbn AT younjulee thalidomideattenuatesmastcellactivationbyupregulatingshp1signalingandinterferingwiththeactionofcrbn |