EMAIL THIS PAGE TO A FRIEND

Biochimica et biophysica acta

S100A4 regulates the Src-tyrosine kinase dependent differentiation of Th17 cells in rheumatoid arthritis.


PMID 25035294

Abstract

To evaluate the role of S100A4, a calcium-binding regulator of nonmuscle myosin assembly, for T-cell responses in rheumatoid arthritis. Arthritis was induced in the methylated bovine serum albumin (mBSA)-immunized mice lacking the entire S100A4 protein (S100A4KO) and in wild-type counterparts treated with short hairpin ribonucleic acid (shRNA)-lentiviral constructs targeting S100A4 (S100A4-shRNA). The severity of arthritis was evaluated morphologically. T-cell subsets were characterized by the expression of master transcription factors, and functionally by proliferation activity and cytokine production. The activity of the Scr-kinases Fyn and Lck was assessed by the autophosphorylation of C-terminal thyrosine and by the phosphorylation of the CD5 cytodomain. The interaction between S100A4 and the CD5 cytodomain was analysed by nuclear magnetic resonance spectrophotometry. S100A4-deficient mice (S100A4KO and S100A4-shRNA) had significantly alleviated morphological signs of arthritis and joint damage. Leukocyte infiltrates in the arthritic joints of S100A4-deficient mice accumulated Foxp3(+) Treg cells, while the number of RORγt(+) and (pTyr705)STAT3(+) cells was reduced. S100A4-deficient mice had a limited formation of Th17-cells with low retinoic acid orphan receptor gamma t (RORγt) mRNA and IL17 production in T-cell cultures. S100A4-deficient mice had a low expression and activity of T-cell receptor (TCR) inhibitor CD5 and low (pTyr705)STAT3 (signal transducer and activator of transcription 3), which led to increased (pTyr352)ZAP-70 (theta-chain associated protein kinase of 70kDa), lymphocyte proliferation and production of IL2. In vitro experiments showed that S100A4 directly binds Lck and Fyn and reciprocally regulates their kinase activity towards the CD5 cytodomain. Spectrometry demonstrates an interaction between the CD5 cytodomain and EF2-binding sites of S100A4. The present study demonstrates that S100A4 plays an important part in the pathogenesis of arthritis. It controls CD5-dependent differentiation of Th17 cells by regulating the activity of the Src-family kinases Lck and Fyn.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

SAB4700041 Anti-CD3, low endotoxin antibody, Mouse monoclonal, clone OKT3, purified immunoglobulin, buffered aqueous solution
SAB4300686
Anti-CD3E antibody produced in rabbit, affinity isolated antibody
C7048
Monoclonal Anti-CD3 antibody produced in mouse, clone UCHT-1, purified immunoglobulin, buffered aqueous solution
SAB4700040 Monoclonal Anti-CD3 antibody produced in mouse, clone OKT3, purified immunoglobulin, buffered aqueous solution
SAB4700044 Monoclonal Anti-CD3 antibody produced in mouse, clone MEM-57, purified immunoglobulin, buffered aqueous solution
SAB4700045 Monoclonal Anti-CD3 antibody produced in mouse, clone MEM-92, purified immunoglobulin, buffered aqueous solution
SAB4700050 Monoclonal Anti-CD3 antibody produced in mouse, clone APA1/1, purified immunoglobulin, buffered aqueous solution
WH0000916M4
Monoclonal Anti-CD3E antibody produced in mouse, clone 4C1, purified immunoglobulin, buffered aqueous solution
AMAB90876
Monoclonal Anti-CD3E antibody produced in mouse, Prestige Antibodies® Powered by Atlas Antibodies, clone CL1466, purified immunoglobulin, buffered aqueous glycerol solution
AMAB90879
Monoclonal Anti-CD3E antibody produced in mouse, Prestige Antibodies® Powered by Atlas Antibodies, clone CL1497, purified immunoglobulin, buffered aqueous glycerol solution
SAB2105133
Anti-CD5, (N-terminal) antibody produced in rabbit, affinity isolated antibody