Cutting Edge: MMP-9 inhibits IL-23p19 expression in dendritic cells by targeting membrane stem cell factor affecting lung IL-17 response.
We reported previously that c-kit ligation by membrane-bound stem cell factor (mSCF) boosts IL-6 production in dendritic cells (DCs) and a Th17-immune response. However, Th17 establishment also requires heterodimeric IL-23, but the mechanisms that regulate IL-23 gene expression in DCs are not fully understood. We show that IL-23p19 gene expression in lung DCs is dependent on mSCF, which is regulated by the metalloproteinase MMP-9. Th1-inducing conditions enhanced MMP-9 activity, causing cleavage of mSCF, whereas the opposite was true for Th17-promoting conditions. In MMP-9(-/-) mice, a Th1-inducing condition could maintain mSCF and enhance IL-23p19 in DCs, promoting IL-17-producing CD4(+) T cells in the lung. Conversely, mSCF cleavage from bone marrow DCs in vitro by rMMP-9 led to reduced IL-23p19 expression under Th17-inducing conditions, with dampening of intracellular AKT phosphorylation. Collectively, these results show that the c-kit/mSCF/MMP-9 axis regulates IL-23 gene expression in DCs to control IL-17 production in the lung.
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Timothy B
TB
Oriss
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.|Department of Immunology, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Nandini
N
Krishnamoorthy
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.|Department of Immunology, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Mahesh
M
Raundhal
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Christina
C
Morse
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Krishnendu
K
Chakraborty
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Anupriya
A
Khare
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Rachael
R
Huff
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.|Department of Immunology, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Prabir
P
Ray
Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.|Department of Immunology, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213.
Anuradha
A
Ray
D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019089:Stem Cell Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
C508841:Il23a protein, mouse; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D019089:Stem Cell Factor; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse