TY - JOUR
T1 - CXCR3-mediated opposite effects of CXCL10 and CXCL4 on TH1 or TH2 cytokine production
AU - Romagnani, Paola
AU - Maggi, Laura
AU - Mazzinghi, Benedetta
AU - Cosmi, Lorenzo
AU - Lasagni, Laura
AU - Liotta, Francesco
AU - Lazzeri, Elena
AU - Angeli, Roberta
AU - Rotondi, Mario
AU - Filì, Lucia
AU - Parronchi, Paola
AU - Serio, Mario
AU - Maggi, Enrico
AU - Romagnani, Sergio
AU - Annunziato, Francesco
PY - 2005/12
Y1 - 2005/12
N2 - Background: Two variants of the CXCR3 receptor exist, one (CXCR3-A) reactive with CXCL9, CXCL10, and CXCL11 and the other (CXCR3-B) also reactive with CXCL4. Both variants are contemporarily expressed by human T cells. Objective: We sought to investigate the in vitro effects of CXCL10 and CXCL4 on the production of TH1 or TH2 cytokines. Methods: The cytokine profile of antigen-specific human CD4+ T-cell lines obtained in the absence or presence of CXCL10 or CXCL4 was evaluated by means of quantitative RT-PCR, flow cytometry, and ELISA. Results: CXCL10 upregulated IFN-γ and downregulated IL-4, IL-5, and IL-13 production, whereas CXCL4 downregulated IFN-γ and upregulated TH2 cytokines. Similar effects were also observed on polyclonally activated pure naive CD4+ T cells. The opposite effects of CXCL10 and CXCL4 on TH1 and T H2 cytokine production were inhibited by an anti-CXCR3 antibody able to neutralize both CXCR3-A and CXCR3-B and were apparently related to the activation of distinct signal transduction pathways. Moreover, CXCL10 upregulated mRNA levels of T-box expressed in T cells and downregulated GATA-3 expression, whereas CXCL4 downregulated T-box expressed in T cells and upregulated GATA-3. Finally, CXCL4, but not CXCL10, induced direct activation of IL-5 and IL-13 promoters. Conclusion: CXCL10 and CXCL4 exert opposite effects on the production of human TH1 and TH2 cytokines, likely through their respective interaction with CXCR3-A or CXCR3-B and the consequent activation of different signal transduction pathways. This might represent an internal regulatory pathway of TH cell responses and might contribute to the modulation of chronic inflammatory reactions, including allergy.
AB - Background: Two variants of the CXCR3 receptor exist, one (CXCR3-A) reactive with CXCL9, CXCL10, and CXCL11 and the other (CXCR3-B) also reactive with CXCL4. Both variants are contemporarily expressed by human T cells. Objective: We sought to investigate the in vitro effects of CXCL10 and CXCL4 on the production of TH1 or TH2 cytokines. Methods: The cytokine profile of antigen-specific human CD4+ T-cell lines obtained in the absence or presence of CXCL10 or CXCL4 was evaluated by means of quantitative RT-PCR, flow cytometry, and ELISA. Results: CXCL10 upregulated IFN-γ and downregulated IL-4, IL-5, and IL-13 production, whereas CXCL4 downregulated IFN-γ and upregulated TH2 cytokines. Similar effects were also observed on polyclonally activated pure naive CD4+ T cells. The opposite effects of CXCL10 and CXCL4 on TH1 and T H2 cytokine production were inhibited by an anti-CXCR3 antibody able to neutralize both CXCR3-A and CXCR3-B and were apparently related to the activation of distinct signal transduction pathways. Moreover, CXCL10 upregulated mRNA levels of T-box expressed in T cells and downregulated GATA-3 expression, whereas CXCL4 downregulated T-box expressed in T cells and upregulated GATA-3. Finally, CXCL4, but not CXCL10, induced direct activation of IL-5 and IL-13 promoters. Conclusion: CXCL10 and CXCL4 exert opposite effects on the production of human TH1 and TH2 cytokines, likely through their respective interaction with CXCR3-A or CXCR3-B and the consequent activation of different signal transduction pathways. This might represent an internal regulatory pathway of TH cell responses and might contribute to the modulation of chronic inflammatory reactions, including allergy.
KW - CXCL10
KW - CXCL4
KW - CXCR3
KW - GATA-3
KW - Immune deviation
KW - T-bet
KW - T1
KW - T2
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UR - http://www.scopus.com/inward/citedby.url?scp=28444466925&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2005.09.035
DO - 10.1016/j.jaci.2005.09.035
M3 - Article
C2 - 16337473
AN - SCOPUS:28444466925
VL - 116
SP - 1372
EP - 1379
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 6
ER -