MafB is a downstream target of the IL-10/STAT3 signaling pathway, involved in the regulation of macrophage de-activation.
In spite of the numerous reports implicating MafB transcription factor in the molecular control of monocyte-macrophage differentiation, the precise genetic program underlying this activity has been, to date, poorly understood. To clarify this issue, we planned a number of experiments that were mainly conducted on human primary macrophages. In this regard, a preliminary gene function study, based on MafB inactivation and over-expression, indicated MMP9 and IL-7R genes as possible targets of the investigated transcription factor. Bioinformatics analysis of their promoter regions disclosed the presence of several putative MARE elements and a combined approach of EMSA and luciferase assay subsequently demonstrated that expression of both genes is indeed activated by MafB through a direct transcription mechanism. Additional investigation, performed with similar procedures to elucidate the biological relevance of our observation, revealed that MafB is a downstream target of the IL-10/STAT3 signaling pathway, normally inducing the macrophage de-activation process. Taken together our data support the existence of a signaling cascade by which stimulation of macrophages with the IL-10 cytokine determines a sequential activation of STAT3 and MafB transcription factors, in turn leading to an up-regulated expression of MMP9 and IL-7R genes.
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy. Electronic address: claudia.gemelli@unimore.it.
Claudia
C
Gemelli
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Tommaso
T
Zanocco Marani
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Silvio
S
Bicciato
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Emilia M C
EM
Mazza
Immunobiology Unit, Institute of Biomedical Technologies, CNR, Pisa, Italy.
Diana
D
Boraschi
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Valentina
V
Salsi
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Vincenzo
V
Zappavigna
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Sandra
S
Parenti
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Tommaso
T
Selmi
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Enrico
E
Tagliafico
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Sergio
S
Ferrari
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41125 Modena, Italy.
Alexis
A
Grande
D001483:Base Sequence; D002460:Cell Line; D015342:DNA Probes; D020868:Gene Silencing; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D008262:Macrophage Activation; D051258:MafB Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D020395:Receptors, Interleukin-7 / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D015342:DNA Probes; C490407:MAFB protein, human; D051258:MafB Transcription Factor; D020395:Receptors, Interleukin-7; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D020783:Matrix Metalloproteinase 7
Gene regulation; IL-10/STAT3 pathway; IL7R; MMP9; MafB; Monocyte activation