title: The expression of interleukin-12 is increased by MAP kinase phosphatase-1 through a mechanism related to interferon regulatory factor 1.
abstract: Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a nuclear tyrosine/threonine phosphatase that inhibits p38 mitogen-activated protein kinase (MAPK) activity. We and others have shown that MKP-1 deficiency leads to excessive activation of innate immunity and inflammatory gene expression. Surprisingly, the present study shows that MKP-1 is a positive regulator of IL-12 expression in macrophages suggesting a stimulatory effect on Th1 type immune response. In the present study, we found that LPS-induced expression of IL-12p40 was lower in primary mouse peritoneal macrophages (PMs) and bone marrow-derived macrophages from MKP-1 deficient mice than in cells from wild-type mice whereas TNF expression was enhanced as expected. Correspondingly, the inhibition of p38 MAPK by pharmacologic inhibitors BIRB 796 and SB 202190 enhanced LPS-induced IL-12p40 production. Silencing of interferon regulatory factor 1 (IRF1) by siRNA inhibited the expression of IL-12p40 in J774 macrophages, showing that IRF1 is an important factor regulating IL-12p40 expression. BIRB 796 enhanced LPS-induced expression of IRF1 in J774 macrophages and in PMs from wild-type mice, and IRF1 expression was reduced in PMs from MKP-1 deficient mice. In conclusions, our results show that MKP-1 increases and p38 MAPK decreases the expression of IL-12 by enhancing the expression of IRF1. MKP-1, through regulation of IRF1 and IL-12, therefore may be an important factor supporting the development of Th1 type of immune response and anti-microbial defense.
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland. riku.korhonen@uta.fi
authors.forename: Riku
authors.initials: R
authors.lastname: Korhonen
authors.forename: Noora
authors.initials: N
authors.lastname: Huotari
authors.forename: Tuija
authors.initials: T
authors.lastname: Hömmö
authors.forename: Tiina
authors.initials: T
authors.lastname: Leppänen
authors.forename: Eeva
authors.initials: E
authors.lastname: Moilanen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D018664:Interleukin-12 / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D018664:Interleukin-12; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse