Prolactin enhances interferon-gamma-induced production of CXC ligand 9 (CXCL9), CXCL10, and CXCL11 in human keratinocytes.
Psoriasis vulgaris is an autoimmune dermatosis characterized by type 1 T cell infiltration. Prolactin may be involved in the pathogenesis of psoriasis. CXC ligand 9 (CXCL9), CXCL10, and CXCL11 recruit type 1 T cells, and their production by keratinocytes is enhanced in psoriatic lesions. CXCL9, CXCL10, and CXCL11 production by keratinocytes depends on nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription (STAT)1 and that of CXCL11 depends on interferon (IFN)-regulatory factor (IRF)-1. We examined in vitro effects of prolactin on CXCL9, CXCL10, and CXCL11 production in human keratinocytes. Although prolactin alone was ineffective, it enhanced IFN-gamma-induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in parallel to the activation of STAT1, NF-kappaB, and IRF-1. Inhibitors of Janus kinase (JAK), p38 MAPK, and MAPK/ERK kinase (MEK) suppressed prolactin- plus IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production and NF-kappaB, STAT1, and IRF-1 activities. Prolactin induced phosphorylation of JAK2 and ERK, whereas IFN-gamma induced phosphorylation of JAK1, JAK2, and p38 MAPK. Prolactin modestly or IFN-gamma greatly induced tyrosine phosphorylation of STAT1, and both were suppressed by JAK inhibitor. Prolactin modestly or IFN-gamma greatly induced serine phosphorylation of STAT1, which was suppressed by MEK or p38 MAPK inhibitor, respectively. Prolactin induced phosphorylation of inhibitory kappaBalpha and NF-kappaB p65, which was suppressed by MEK inhibitor. These results suggest that prolactin may enhance IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in keratinocytes via activation of STAT1, NF-kappaB, and IRF-1 through JAK2 and MEK/ERK pathways. Prolactin may promote type 1 T cell infiltration into psoriatic lesions via these chemokines.
Kanda
Naoko
N
Department of Dermatology, Teikyo University School of Medicine, Itabashi-Ku, Tokyo 173-8605, Japan. nmk@med.teikyo-u.ac.jp
Watanabe
Shinichi
S
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D011388:Prolactin / Q000494:pharmacology*; D011565:Psoriasis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D011981:Receptors, Prolactin / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000998:Antiviral Agents; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D011981:Receptors, Prolactin; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma; D011388:Prolactin; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases