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Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype

Christophi, George P ; Panos, Michael ; Hudson, Chad A ; Christophi, Rebecca L ; Gruber, Ross C ; Mersich, Akos T ; Blystone, Scott D ; Jubelt, Burk ; Massa, Paul T

Laboratory investigation, 2009-07, Vol.89 (7), p.742-759 [Periódico revisado por pares]

New York, NY: Elsevier Inc

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Título:
Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype
Autor: Christophi, George P ; Panos, Michael ; Hudson, Chad A ; Christophi, Rebecca L ; Gruber, Ross C ; Mersich, Akos T ; Blystone, Scott D ; Jubelt, Burk ; Massa, Paul T
Assuntos: Adult ; autoimmunity/multiple sclerosis ; Base Sequence ; Biological and medical sciences ; Biotechnology ; Case-Control Studies ; cytokines ; Cytokines - antagonists & inhibitors ; Cytokines - genetics ; Cytokines - metabolism ; Demyelinating Diseases - enzymology ; Demyelinating Diseases - genetics ; Demyelinating Diseases - pathology ; DNA Primers - genetics ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Expression ; human ; Humans ; In Vitro Techniques ; inflammation ; Inflammation - enzymology ; Inflammation - genetics ; Inflammation - pathology ; Investigative techniques, diagnostic techniques (general aspects) ; macrophages ; Macrophages - enzymology ; Male ; Medical sciences ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting - enzymology ; Multiple Sclerosis, Relapsing-Remitting - genetics ; Multiple Sclerosis, Relapsing-Remitting - pathology ; NF-kappa B - metabolism ; Phenotype ; Promoter Regions, Genetic ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - deficiency ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; RNA, Small Interfering - genetics ; STAT1 Transcription Factor - metabolism ; STAT6 Transcription Factor - metabolism ; transcription factors
É parte de: Laboratory investigation, 2009-07, Vol.89 (7), p.742-759
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descrição: Recent studies in mice have demonstrated that the protein tyrosine phosphatase SHP-1 is a crucial negative regulator of proinflammatory cytokine signaling, TLR signaling, and inflammatory gene expression. Furthermore, mice genetically lacking SHP-1 (me/me) display a profound susceptibility to inflammatory CNS demyelination relative to wild-type mice. In particular, SHP-1 deficiency may act predominantly in inflammatory macrophages to increase CNS demyelination as SHP-1-deficient macrophages display coexpression of inflammatory effector molecules and increased demyelinating activity in me/me mice. Recently, we reported that PBMCs of multiple sclerosis (MS) patients have a deficiency in SHP-1 expression relative to normal control subjects indicating that SHP-1 deficiency may play a similar role in MS as to that seen in mice. Therefore, it became essential to examine the specific expression and function of SHP-1 in macrophages from MS patients. Herein, we document that macrophages of MS patients have deficient SHP-1 protein and mRNA expression relative to those of normal control subjects. To examine functional consequences of the lower SHP-1, the activation of STAT6, STAT1, and NF-κB was quantified and macrophages of MS patients showed increased activation of these transcription factors. In accordance with this observation, several STAT6-, STAT1-, and NF-κB-responsive genes that mediate inflammatory demyelination were increased in macrophages of MS patients following cytokine and TLR agonist stimulation. Supporting a direct role of SHP-1 deficiency in altered macrophage function, experimental depletion of SHP-1 in normal subject macrophages resulted in an increased STAT/NF-κB activation and increased inflammatory gene expression to levels seen in macrophages of MS patients. In conclusion, macrophages of MS patients display a deficiency of SHP-1 expression, heightened activation of STAT6, STAT1, and NF-κB and a corresponding inflammatory profile that may be important in controlling macrophage-mediated demyelination in MS.
Editor: New York, NY: Elsevier Inc
Idioma: Inglês

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Macrophages of multiple sclerosis patients display deficient SHP-1 expression and enhanced inflammatory phenotype

Christophi, George P ; Panos, Michael ; Hudson, Chad A ; Christophi, Rebecca L ; Gruber, Ross C ; Mersich, Akos T ; Blystone, Scott D ; Jubelt, Burk ; Massa, Paul T

New York, NY: Elsevier Inc

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