IL-8 promotes inflammatory mediators and stimulates activation of p38 MAPK/ERK-NF-κB pathway and reduction of JNK in HNSCC

// Leong-Perng Chan 1, 2 , Cheng Liu 3, 4 , Feng-Yu Chiang 2 , Ling-Feng Wang 2 , Ka-Wo Lee 2 , Wan-Ting Chen 5 , Po-Lin Kuo 1, 6 and Chia-Hua Liang 5 1 Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan 2 Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan 3 Division of Plastic Surgery & HBOT Center, Chi Mei Medical Center, Tainan, Taiwan 4 Department of Electrical Engineering, Southern Taiwan University of Science & Technology, Tainan, Taiwan 5 Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan 6 Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung, Taiwan Correspondence to: Po-Lin Kuo, email: kuopolin@seed.net.tw Chia-Hua Liang, email: tinna_ling@mail.cnu.edu.tw Keywords: HNSCC, IL-8, inflammation, MAPK Received: November 30, 2016 Accepted: March 08, 2017 Published: April 07, 2017 ABSTRACT This investigation identifies interleukin 8 (IL-8) as the main inflammatory mediator in head and neck squamous cell carcinoma (HNSCC). The expressions of chemokines of IL-8, IL-1β and IL-6 and the cytokines of tumor necrosis factor-α (TNF-α) were higher in HNSCC patient tissues than in non-cancerous matched tissues (NCMT) whereas the expression of IL-10 was lower. IL-8 is most highly expressed in the tissues of patients with HNSCC. Treatment of HNSCC cells with IL-8 increased the secretion of IL-1β, IL-6 and TNF-α and reduced IL-10 expression; the increase in the expression of IL-1β was particularly considerable. IL-8 silencing by siRNA reduced IL-1β expression in HNSCC cells, suggesting that IL-8 as a main inflammatory mediator improved IL-1β expression in HNSCC. The expressions of p-p38 mitogen-activated protein kinases (MAPK) and p-extracellular signal regulated kinase (p-ERK) were higher and that of p-c-Jun-NH2-terminal kinase (p-JNK) was lower in HNSCC patient tissues than in NCMT. IL-8 treatment induced p-p38 MAPK and p-ERK expression, but reduced p-JNK expressions in HNSCC cells. IL-8 siRNA suppressed p38 MAPK and ERK but increased JNK expression in HNSCC cells. Exposure of SCC25 cells to IL-8, increased the expressions of p-IκB-α and nuclear factor (NF)-κB, suggesting that IL-8 regulates inflammatory response by modulating the MAPK and NF-κB pathway in HNSCC cells. IL-8 promotes the migration of SCC25 cells and increases matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. These results reveal that IL-8 is the major stimulus of inflammatory mediation in HNSCC progression and migration by activating the p38 MAPK/ERK-NF-κB pathway and reducing JNK.