Loss of SOCS7 in mice results in severe cutaneous disease and increased mast cell activation.
The Suppressor of Cytokine Signaling (SOCS) protein family plays a central role in the negative regulation of cytokine action and has been implicated in the development of atopic diseases. Lack of SOCS7 is associated with severe skin disease in mice. We sought to explore the underlying mechanisms resulting in this phenotype. Skin samples were analyzed and serum immunoglobulin production was measured. Cytokine production by bone marrow derived mast cells was determined by ELISA. Mast cell thymic stromal lymphopoietin (TSLP) production was assessed by quantitative real-time PCR. Data obtained revealed that Socs7(-/-) mice have increased serum IgE and IgG(1) production and exhibit an increased mast cell infiltrate, as well as un-provoked mast cell degranulation in the dermis as compared to controls. In vitro, bone marrow derived mast cells from Socs7(-/-) mice are hyperactive to IgE-mediated stimuli, with elevated production of pro-inflammatory cytokines (IL-13, IL-6, TNF-alpha). Further, activated Socs7(-/-) bone marrow derived mast cells have increased IL-7Ralpha transcript, which is part of the heterodimeric receptor for TSLP. Finally, lack of SOCS7 was accompanied by an increase in TSLP mRNA and protein production by mast cells following FcepsilonRI aggregation. These data implicate SOCS7 in the modulation of allergic inflammation and demonstrate that SOCS7 is involved in the regulation of TSLP signaling in mast cells.
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Judit
J
Knisz
Alex
A
Banks
Lisa
L
McKeag
Dean D
DD
Metcalfe
Paul B
PB
Rothman
Jared M
JM
Brown
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D018793:Interleukin-13 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017455:Receptors, IgE / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012871:Skin Diseases / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D007074:Immunoglobulin G; D018793:Interleukin-13; D015850:Interleukin-6; D017455:Receptors, IgE; D020395:Receptors, Interleukin-7; C506118:SOCS7 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; C415350:interleukin-7 receptor, alpha chain; D007073:Immunoglobulin E; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse