AP-1 Activates KCNN4-mediated Ca2 Signaling to Induce the Th1/Th17 Differentiation of CD4 Cells in Chronic Non-bacterial Prostatitis

Overview

Journal Cell Biol Toxicol

Publisher Springer

Specialties Cell Biology
Toxicology

Date 2024 Dec 27

PMID 39729199

Authors

Jingfei Teng

Zhuomin Jia

Feng Gao

Yawei Guan

Li Yao

Chong Ma

Zhihui Li

Xing Ai

Affiliations

Soon will be listed here.

Abstract

The intraprostatic inflammatory infiltrate is characterized by Th1 CD4 T cells, and its molecular mechanism is not well defined. This study explored the mechanisms responsible for the alteration of Th1/Th17 differentiation of CD4 T cells in chronic non-bacterial prostatitis (CNP). CNP rats were induced by the administration of testosterone and 17β-estradiol. The Th1/Th17 cell percentage was increased in the prostate tissue of CNP rats, which was accompanied by increased IL-2, IFN-γ, IL-17A, and IL-22 levels. Transcriptome sequencing was performed, followed by KEGG pathway enrichment analysis. Activator protein-1 (AP-1) was enhanced in CD4 T cells from CNP rats, and its inhibitor SR11302 suppressed Th1/Th17 differentiation and delayed CNP. AP-1 transcriptionally activated the expression of KCNN4, which potentiated mTORC1 in CD4 T cells by enhancing Ca2 signaling, thereby promoting Th1/Th17 differentiation. Rapamycin-mediated autophagy activation reversed AP-1/KCNN4/mTORC1-promoted Th1/Th17 differentiation, thereby inhibiting CNP. These results suggest that AP-1-mediated KCNN4 transcription promotes the inhibition of autophagy by mTORC1 through Ca2 signaling, which supports Th1/Th17 differentiation of CD4 T cells, resulting in the transformation of CNP to prostatic intraepithelial neoplasia and adenocarcinoma.

References

Liu Y, Wazir J, Tang M, Ullah R, Chen Y, Chen T . Experimental autoimmune prostatitis: different antigens induction and antigen-specific therapy. Int Urol Nephrol. 2020; 53(4):607-618. DOI: 10.1007/s11255-020-02703-8. View

Ebersbach C, Beier A, Thomas C, Erb H . Impact of STAT Proteins in Tumor Progress and Therapy Resistance in Advanced and Metastasized Prostate Cancer. Cancers (Basel). 2021; 13(19). PMC: 8508518. DOI: 10.3390/cancers13194854. View

Franco J, Turk T, Jung J, Xiao Y, Iakhno S, Garrote V . Non-pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome. Cochrane Database Syst Rev. 2018; 1:CD012551. PMC: 6491290. DOI: 10.1002/14651858.CD012551.pub2. View

Su Y, Lu J, Chen X, Liang C, Luo P, Qin C . Rapamycin Alleviates Hormone Imbalance-Induced Chronic Nonbacterial Inflammation in Rat Prostate Through Activating Autophagy via the mTOR/ULK1/ATG13 Signaling Pathway. Inflammation. 2018; 41(4):1384-1395. DOI: 10.1007/s10753-018-0786-7. View

Niu H, Wang J, Li H, He P . Rapamycin potentiates cytotoxicity by docetaxel possibly through downregulation of Survivin in lung cancer cells. J Exp Clin Cancer Res. 2011; 30:28. PMC: 3065416. DOI: 10.1186/1756-9966-30-28. View

Chen L, Zhang M, Liang C . Chronic Prostatitis and Pelvic Pain Syndrome: Another Autoimmune Disease?. Arch Immunol Ther Exp (Warsz). 2021; 69(1):24. DOI: 10.1007/s00005-021-00628-3. View

Sfanos K, Yegnasubramanian S, Nelson W, De Marzo A . The inflammatory microenvironment and microbiome in prostate cancer development. Nat Rev Urol. 2017; 15(1):11-24. DOI: 10.1038/nrurol.2017.167. View

Chatzileontiadou D, Sloane H, Nguyen A, Gras S, Grant E . The Many Faces of CD4 T Cells: Immunological and Structural Characteristics. Int J Mol Sci. 2020; 22(1). PMC: 7796221. DOI: 10.3390/ijms22010073. View

Bieerkehazhi S, Fan Y, West S, Tewari R, Ko J, Mills T . Ca2+-dependent protein acyltransferase DHHC21 controls activation of CD4+ T cells. J Cell Sci. 2021; 135(5). PMC: 8214660. DOI: 10.1242/jcs.258186. View

10.

Ohya S, Niwa S, Kojima Y, Sasaki S, Sakuragi M, Kohri K . Intermediate-conductance Ca2+-activated K+ channel, KCa3.1, as a novel therapeutic target for benign prostatic hyperplasia. J Pharmacol Exp Ther. 2011; 338(2):528-36. DOI: 10.1124/jpet.111.182782. View

11.

Park H, Choi S, Back Y, Lee K, Choi H, Kim H . RpfE-Induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation. Int J Mol Sci. 2021; 22(14). PMC: 8304802. DOI: 10.3390/ijms22147535. View

12.

Zang L, Tian F, Yao Y, Chen Y, Shen Y, Han M . Qianliexin capsule exerts anti-inflammatory activity in chronic non-bacterial prostatitis and benign prostatic hyperplasia via NF-κB and inflammasome. J Cell Mol Med. 2021; 25(12):5753-5768. PMC: 8184730. DOI: 10.1111/jcmm.16599. View

13.

Zhang M, Hoyle R, Ma Z, Sun B, Cai W, Cai H . FOSL1 promotes metastasis of head and neck squamous cell carcinoma through super-enhancer-driven transcription program. Mol Ther. 2021; 29(8):2583-2600. PMC: 8353207. DOI: 10.1016/j.ymthe.2021.03.024. View

14.

Deleyto-Seldas N, Efeyan A . The mTOR-Autophagy Axis and the Control of Metabolism. Front Cell Dev Biol. 2021; 9:655731. PMC: 8281972. DOI: 10.3389/fcell.2021.655731. View

15.

Murphy S, Schaeffer A, Done J, Quick M, Acar U, Thumbikat P . Commensal bacterial modulation of the host immune response to ameliorate pain in a murine model of chronic prostatitis. Pain. 2017; 158(8):1517-1527. PMC: 6019276. DOI: 10.1097/j.pain.0000000000000944. View

16.

Nam Y, Downey M, Rahman M, Cui M, Zhang M . Channelopathy of small- and intermediate-conductance Ca-activated K channels. Acta Pharmacol Sin. 2022; 44(2):259-267. PMC: 9889811. DOI: 10.1038/s41401-022-00935-1. View

17.

Weng W, Kuo P, Brown D, Scofield B, Furnas D, Paraiso H . 4-Ethylguaiacol modulates neuroinflammation and Th1/Th17 differentiation to ameliorate disease severity in experimental autoimmune encephalomyelitis. J Neuroinflammation. 2021; 18(1):110. PMC: 8111955. DOI: 10.1186/s12974-021-02143-w. View

18.

Ye N, Ding Y, Wild C, Shen Q, Zhou J . Small molecule inhibitors targeting activator protein 1 (AP-1). J Med Chem. 2014; 57(16):6930-48. PMC: 4148154. DOI: 10.1021/jm5004733. View

19.

Polackwich A, Shoskes D . Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy. Prostate Cancer Prostatic Dis. 2016; 19(2):132-8. DOI: 10.1038/pcan.2016.8. View

20.

Park M, Moon S, Lee S, Kim E, Yang E, Min J . Blocking activator protein 1 activity in donor cells reduces severity of acute graft-versus-host disease through reciprocal regulation of IL-17-producing T cells/regulatory T cells. Biol Blood Marrow Transplant. 2014; 20(8):1112-20. DOI: 10.1016/j.bbmt.2014.04.031. View