SHARPIN is essential for cytokine production, NF-κB signaling, and induction of Th1 differentiation by dendritic cells

Zhe Wang, Anna Sokolovska, Rosemarie Seymour, John P. Sundberg, Harm HogenEsch

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Spontaneous mutations of the Sharpin (SHANK-associated RH domain-interacting protein, other aliases: Rbckl1, Sipl1) gene in mice result in systemic inflammation that is characterized by chronic proliferative dermatitis and dysregulated secretion of T helper1 (Th1) and Th2 cytokines. The cellular and molecular mechanisms underlying this inflammatory phenotype remain elusive. Dendritic cells may contribute to the initiation and progression of the phenotype of SHARPIN-deficient mice because of their pivotal role in innate and adaptive immunity. Here we show by flow cytometry that SHARPIN- deficiency did not alter the distribution of different DC subtypes in the spleen. In response to TOLL-like receptor (TLR) agonists LPS and poly I:C, cultured bone marrow-derived dendritic cells (BMDC) from WT and mutant mice exhibited similar increases in expression of co-stimulatory molecules CD40, CD80, and CD86. However, stimulated SHARPIN-deficient BMDC had reduced transcription and secretion of pro-inflammatory mediators IL6, IL12P70, GMCSF, and nitric oxide. Mutant BMDC had defective activation of NF-κB signaling, whereas the MAPK1/3 (ERK1/2) and MAPK11/12/13/14 (p38 MAP kinase isoforms) and TBK1 signaling pathways were intact. A mixed lymphocyte reaction showed that mutant BMDC only induced a weak Th1 immune response but stimulated increased Th2 cytokine production from allogeneic naïve CD4 + T cells. In conclusion, loss of Sharpin in mice significantly affects the immune function of DC and this may partially account for the systemic inflammation and Th2-biased immune response.

Original languageEnglish (US)
Article numbere31809
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 14 2012
Externally publishedYes

Fingerprint

dendritic cells
Dendritic Cells
cytokines
bone marrow
Cytokines
Bone
Bone Marrow
mice
mutants
inflammation
Dermatitis
immune response
secretion
CD14 Antigens
Inflammation
Phenotype
phenotype
polyinosinic-polycytidylic acid
Poly I-C
Mixed Lymphocyte Culture Test

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

SHARPIN is essential for cytokine production, NF-κB signaling, and induction of Th1 differentiation by dendritic cells. / Wang, Zhe; Sokolovska, Anna; Seymour, Rosemarie; Sundberg, John P.; HogenEsch, Harm.

In: PLoS One, Vol. 7, No. 2, e31809, 14.02.2012.

Research output: Contribution to journalArticle

Wang, Zhe ; Sokolovska, Anna ; Seymour, Rosemarie ; Sundberg, John P. ; HogenEsch, Harm. / SHARPIN is essential for cytokine production, NF-κB signaling, and induction of Th1 differentiation by dendritic cells. In: PLoS One. 2012 ; Vol. 7, No. 2.
@article{02f13a93eae3442baace73becbe56620,
title = "SHARPIN is essential for cytokine production, NF-κB signaling, and induction of Th1 differentiation by dendritic cells",
abstract = "Spontaneous mutations of the Sharpin (SHANK-associated RH domain-interacting protein, other aliases: Rbckl1, Sipl1) gene in mice result in systemic inflammation that is characterized by chronic proliferative dermatitis and dysregulated secretion of T helper1 (Th1) and Th2 cytokines. The cellular and molecular mechanisms underlying this inflammatory phenotype remain elusive. Dendritic cells may contribute to the initiation and progression of the phenotype of SHARPIN-deficient mice because of their pivotal role in innate and adaptive immunity. Here we show by flow cytometry that SHARPIN- deficiency did not alter the distribution of different DC subtypes in the spleen. In response to TOLL-like receptor (TLR) agonists LPS and poly I:C, cultured bone marrow-derived dendritic cells (BMDC) from WT and mutant mice exhibited similar increases in expression of co-stimulatory molecules CD40, CD80, and CD86. However, stimulated SHARPIN-deficient BMDC had reduced transcription and secretion of pro-inflammatory mediators IL6, IL12P70, GMCSF, and nitric oxide. Mutant BMDC had defective activation of NF-κB signaling, whereas the MAPK1/3 (ERK1/2) and MAPK11/12/13/14 (p38 MAP kinase isoforms) and TBK1 signaling pathways were intact. A mixed lymphocyte reaction showed that mutant BMDC only induced a weak Th1 immune response but stimulated increased Th2 cytokine production from allogeneic na{\"i}ve CD4 + T cells. In conclusion, loss of Sharpin in mice significantly affects the immune function of DC and this may partially account for the systemic inflammation and Th2-biased immune response.",
author = "Zhe Wang and Anna Sokolovska and Rosemarie Seymour and Sundberg, {John P.} and Harm HogenEsch",
year = "2012",
month = "2",
day = "14",
doi = "10.1371/journal.pone.0031809",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - SHARPIN is essential for cytokine production, NF-κB signaling, and induction of Th1 differentiation by dendritic cells

AU - Wang, Zhe

AU - Sokolovska, Anna

AU - Seymour, Rosemarie

AU - Sundberg, John P.

AU - HogenEsch, Harm

PY - 2012/2/14

Y1 - 2012/2/14

N2 - Spontaneous mutations of the Sharpin (SHANK-associated RH domain-interacting protein, other aliases: Rbckl1, Sipl1) gene in mice result in systemic inflammation that is characterized by chronic proliferative dermatitis and dysregulated secretion of T helper1 (Th1) and Th2 cytokines. The cellular and molecular mechanisms underlying this inflammatory phenotype remain elusive. Dendritic cells may contribute to the initiation and progression of the phenotype of SHARPIN-deficient mice because of their pivotal role in innate and adaptive immunity. Here we show by flow cytometry that SHARPIN- deficiency did not alter the distribution of different DC subtypes in the spleen. In response to TOLL-like receptor (TLR) agonists LPS and poly I:C, cultured bone marrow-derived dendritic cells (BMDC) from WT and mutant mice exhibited similar increases in expression of co-stimulatory molecules CD40, CD80, and CD86. However, stimulated SHARPIN-deficient BMDC had reduced transcription and secretion of pro-inflammatory mediators IL6, IL12P70, GMCSF, and nitric oxide. Mutant BMDC had defective activation of NF-κB signaling, whereas the MAPK1/3 (ERK1/2) and MAPK11/12/13/14 (p38 MAP kinase isoforms) and TBK1 signaling pathways were intact. A mixed lymphocyte reaction showed that mutant BMDC only induced a weak Th1 immune response but stimulated increased Th2 cytokine production from allogeneic naïve CD4 + T cells. In conclusion, loss of Sharpin in mice significantly affects the immune function of DC and this may partially account for the systemic inflammation and Th2-biased immune response.

AB - Spontaneous mutations of the Sharpin (SHANK-associated RH domain-interacting protein, other aliases: Rbckl1, Sipl1) gene in mice result in systemic inflammation that is characterized by chronic proliferative dermatitis and dysregulated secretion of T helper1 (Th1) and Th2 cytokines. The cellular and molecular mechanisms underlying this inflammatory phenotype remain elusive. Dendritic cells may contribute to the initiation and progression of the phenotype of SHARPIN-deficient mice because of their pivotal role in innate and adaptive immunity. Here we show by flow cytometry that SHARPIN- deficiency did not alter the distribution of different DC subtypes in the spleen. In response to TOLL-like receptor (TLR) agonists LPS and poly I:C, cultured bone marrow-derived dendritic cells (BMDC) from WT and mutant mice exhibited similar increases in expression of co-stimulatory molecules CD40, CD80, and CD86. However, stimulated SHARPIN-deficient BMDC had reduced transcription and secretion of pro-inflammatory mediators IL6, IL12P70, GMCSF, and nitric oxide. Mutant BMDC had defective activation of NF-κB signaling, whereas the MAPK1/3 (ERK1/2) and MAPK11/12/13/14 (p38 MAP kinase isoforms) and TBK1 signaling pathways were intact. A mixed lymphocyte reaction showed that mutant BMDC only induced a weak Th1 immune response but stimulated increased Th2 cytokine production from allogeneic naïve CD4 + T cells. In conclusion, loss of Sharpin in mice significantly affects the immune function of DC and this may partially account for the systemic inflammation and Th2-biased immune response.

UR - http://www.scopus.com/inward/record.url?scp=84863133303&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863133303&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0031809

DO - 10.1371/journal.pone.0031809

M3 - Article

C2 - 22348129

AN - SCOPUS:84863133303

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e31809

ER -