title: IL-4, but not IL-13, modulates TARC (thymus and activation-regulated chemokine)/CCL17 and IP-10 (interferon-induced protein of 10kDA)/CXCL10 release by TNF-alpha and IFN-gamma in HaCaT cell line.
abstract: It is known that both interleukin-4 (IL-4) and IL-13 are produced by Th2-type cells and share similar biological functions with each other. However, recently accumulated evidences have revealed that IL-4 may be involved in the Th1-type response. Both thymus and activation-regulated chemokine (TARC/CCL17), a ligand for CC chemokine receptor 4 that is mainly expressed on Th2-type cells, and interferon-induced protein of 10kDa (IP-10/CXCL10), a ligand for CXC chemokine receptor 3 that is mainly expressed on Th1-type cells, are produced by keratinocytes after the stimulation with the primary cytokines such as tumor necrotic factor-alpha (TNF-alpha) and/or interferon-gamma (IFN-gamma). In this study, we investigated the regulation of TARC or IP-10 production from HaCaT cells, an immortalized human keratinocyte cell line, after stimulation with TNF-alpha, IFN-gamma, IL-4 and/or IL-13. Without stimulation, HaCaT cells did not produce TARC. When both TNF-alpha and IFN-gamma were added, they increased synergistically (P<0.003). In addition, when HaCaT cells were stimulated with IL-4, but not IL-13, in combination with TNF-alpha and IFN-gamma, the supernatant TARC levels significantly decreased compared to those with both TNF-alpha and IFN-gamma (P<0.009). This inhibition was completely abolished with the addition of neutralizing anti-IL-4 antibody. The supernatant IP-10 levels also increased synergistically by stimulation with TNF-alpha and IFN-gamma for 24h (P<0.001). When IL-4, but not IL-13, was added to the medium and the cells were co-cultured with these cytokines, the IP-10 levels significantly increased compared to those with both TNF-alpha and IFN-gamma (P<0.04). Furthermore, the effects of IL-4 on TARC and IP-10 production in these cells were detected in a dose-dependent manner. These data strongly suggest that IL-4 may act not only as a mediator of Th1-type response but also as a down-regulator of Th2-type response in terms of the regulation of chemokine production by HaCaT cells.
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. kakinumat-der@h.u-tokyo.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kakinuma
authors.forename: Koichiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Motoshi
authors.initials: M
authors.lastname: Wakugawa
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Yano
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Saeki
authors.forename: Hideshi
authors.initials: H
authors.lastname: Torii
authors.forename: Mayumi
authors.initials: M
authors.lastname: Komine
authors.forename: Akihiko
authors.initials: A
authors.lastname: Asahina
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tamaki
mesh_terms: D002461:Cell Line, Transformed; D054414:Chemokine CCL17; D054357:Chemokine CXCL10; D019742:Chemokines, CC / Q000502:physiology*; D019743:Chemokines, CXC / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D018793:Interleukin-13 / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: C106230:CCL17 protein, human; D054414:Chemokine CCL17; D054357:Chemokine CXCL10; D019742:Chemokines, CC; D019743:Chemokines, CXC; D018793:Interleukin-13; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma