{"doi":"10.1002/pros.24026","title":"Promotion of epithelial hyperplasia by interleukin‐8—CXCR axis in human prostate","abstract":"BACKGROUND: The clinical manifestation of benign prostatic hyperplasia (BPH) is causally linked to the inflammatory microenvironment and proliferation of epithelial and stromal cells in the prostate transitional zone. The CXC-chemokine interleukin-8 (IL-8) contributes to inflammation. We evaluated the expression of inflammatory cytokines in clinical specimens, primary cultures, and prostatic lineage cell lines. We investigated whether IL-8 via its receptor system (IL-8 axis) promotes BPH. METHODS: The messenger RNA and protein expression of chemokines, including components of the IL-8 axis, were measured in normal prostate (NP; n = 7) and BPH (n = 21), urine (n = 24) specimens, primary cultures, prostatic lineage epithelial cell lines (NHPrE1, BHPrE1, BPH-1), and normal prostate cells (RWPE-1). The functional role of the IL-8 axis in prostate epithelial cell growth was evaluated by CRISPR/Cas9 gene editing. The effect of a combination with two natural compounds, oleanolic acid (OA) and ursolic acid (UA), was evaluated on the expression of the IL-8 axis and epithelial cell growth. RESULTS: Among the 19 inflammatory chemokines and chemokine receptors we analyzed, levels of IL-8 and its receptors (CXCR1, CXCR2), as well as, of CXCR7, a receptor for CXCL12, were 5- to 25-fold elevated in BPH tissues when compared to NP tissues (P ≤ .001). Urinary IL-8 levels were threefold to sixfold elevated in BPH patients, but not in asymptomatic males and females with lower urinary tract symptoms (P ≤ .004). The expression of the IL-8 axis components was confined to the prostate luminal epithelial cells in both normal and BPH tissues. However, these components were elevated in BPH-1 and primary explant cultures as compared to RWPE-1, NHPrE1, and BHPrE1 cells. Knockout of CXCR7 reduced IL-8, and CXCR1 expression by 4- to 10-fold and caused greater than or equal to 50% growth inhibition in BPH-1 cells. Low-dose OA + UA combination synergistically inhibited the growth of BPH-1 and BPH primary cultures. In the combination, the drug reduction indices for UA and OA were 16.4 and 7852, respectively, demonstrating that the combination was effective in inhibiting BPH-1 growth at significantly reduced doses of UA or OA alone. CONCLUSION: The IL-8 axis is a promotor of BPH pathogenesis. Low-dose OA + UA combination inhibits BPH cell growth by inducing autophagy and reducing IL-8 axis expression in BPH-epithelial cells.","journal":"The Prostate","year":2020,"id":71018,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":377473,"name":"Sarrah L. Hasanali","orcid":null,"position":1,"is_corresponding":false},{"id":53187,"name":"Jiaojiao Wang","orcid":"0000-0002-2265-7957","position":2,"is_corresponding":false},{"id":375835,"name":"Georgios Kallifatidis","orcid":"0000-0003-3602-9537","position":3,"is_corresponding":false},{"id":375836,"name":"Daley S. Morera","orcid":"0000-0001-5298-5110","position":4,"is_corresponding":false},{"id":375837,"name":"Andre R. Jordan","orcid":"0000-0001-6866-5728","position":5,"is_corresponding":false},{"id":325364,"name":"Martha K. Terris","orcid":"0000-0002-3843-7270","position":6,"is_corresponding":false},{"id":325366,"name":"Zachary Klaassen","orcid":"0000-0001-7392-8916","position":7,"is_corresponding":false},{"id":249679,"name":"Roni J. Bollag","orcid":"0000-0003-4963-6619","position":8,"is_corresponding":false},{"id":375838,"name":"Vinata B. Lokeshwar","orcid":"0000-0002-9909-6545","position":9,"is_corresponding":false},{"id":375839,"name":"Bal L. Lokeshwar","orcid":"0000-0002-1763-4718","position":10,"is_corresponding":false},{"id":377472,"name":"Diandra K. Smith","orcid":null,"position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-18T21:43:57.004133Z","pmid":"32542667","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}