Regulation of avoidant behaviors and pain by the anti-inflammatory tyrosine phosphatase SHP-1

Hudson, Chad A.; Christophi, George P.; Cao, Ling; Gruber, Ross C.; Massa, Paul T.

doi:10.1017/s1740925x07000476

Cited by 8 publications

(7 citation statements)

References 40 publications

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“…IFN-β treatment of MS patients did not change the levels of IL-4, but significantly decreased plasma levels of IL-13. In addition, we quantified the secretion of the NF-κB-responsive pro-inflammatory cytokines TNF-α and IL-6, since it was previously shown that a deficiency in SHP-1 leads to higher expression of these cytokines [22; 40; 68; 74; 76; 77]. The plasma levels of TNF-α and IL-6 were significantly higher in MS patients compared to normal subjects.…”

Section: Resultsmentioning

confidence: 99%

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Interferon-β treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1

Christophi¹,

Panos²,

Hudson³

et al. 2009

Clinical Immunology

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Interferon-β is a current treatment for multiple sclerosis (MS). Interferon-β is thought to exert its therapeutic effects on MS by down-modulating the immune response by multiple potential pathways. Here, we document that treatment of MS patients with interferon β-1a (Rebif) results in a significant increase in the levels and function of the protein tyrosine phosphatase SHP-1 in PBMCs. SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and CNS demyelination as evidenced in mice deficient in SHP-1. In order to examine the functional significance of SHP-1 induction in MS PBMCs, we analyzed the activity of proinflammatory signaling molecules STAT1, STAT6, and NF-κB, which are known SHP-1 targets. Interferon-β treatment in vivo resulted in decreased NF-κB and STAT6 activation and increased STAT1 activation. Further analysis in vitro showed that cultured PBMCs of MS patients and normal subjects had a significant SHP-1 induction following interferon-β treatment that correlated with decreased NF-κB and STAT6 activation. Most importantly, experimental depletion of SHP-1 in cultured PBMCs abolished the anti-inflammatory effects of interferon-β treatment, indicating that SHP-1 is a predominant mediator of interferon-β activity. In conclusion, interferon-β treatment upregulates SHP-1 expression resulting in decreased transcription factor activation and inflammatory gene expression important in MS pathogenesis.

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Section: Resultsmentioning

confidence: 99%

“…Arginase enzymatic activity was measured as previously described [68]. Briefly, PBMCs were lysed in RIPA buffer and incubated in 10 mM MnCl 2 and 0.5 M L-arginine at 37°C for 75 min.…”

Section: Methodsmentioning

confidence: 99%

Interferon-β treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1

Christophi¹,

Panos²,

Hudson³

et al. 2009

Clinical Immunology

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“…In addition, we quantified the secretion of the NF-kBresponsive proinflammatory cytokines TNF-a and IL-6 from macrophages of MS patients compared to normal subjects, because it was previously shown that a deficiency in SHP-1 leads to higher expression of these cytokines. 9,27,62,[64][65][66] Macrophages were cultured for 18 h with either media alone, TLR ligands, or TNF-a and the supernatants were analyzed for the presence of TNF-a or IL-6 (Figure 5b and c). Constitutively, the levels of TNF-a and IL-6 were slightly but significantly elevated in supernatants of macrophages from MS patients compared to normal subjects.…”

Section: Elevated Expression Of Nf-jb Dna-binding Activity and Tnf-a/mentioning

confidence: 92%

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

Christophi

Panos

Hudson

et al. 2009

Laboratory Investigation

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Recent studies in mice have demonstrated that the protein tyrosine phosphatase SHP-1 is a crucial negative regulator of pro-inflammatory 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 co-expression 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.

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“…31 Briefly, PBMCs were lysed in RIPA buffer and incubated in 10 mM MnCl 2 and 0.5 M L-arginine at 371C for 75 min. After the assay was stopped by addition of H 3 PO 4 , 1-phenyl-1,2-propanedione-2-oxime (Sigma, St Louis, MO, USA) was added and the samples were incubated at 1001C for 60 min.…”

Section: Transduction Of Shp-1-expresssing Lentiviral Vectormentioning

confidence: 99%

SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients

Christophi

Hudson

Gruber

et al. 2008

Laboratory Investigation

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Recent studies in mice have demonstrated that the protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling, inflammatory gene expression, and demyelination in central nervous system. The present study investigates a possible similar role for SHP-1 in the human disease multiple sclerosis (MS). The levels of SHP-1 protein and mRNA in PBMCs of MS patients were significantly lower compared to normal subjects. Moreover, promoter II transcripts, expressed from one of two known promoters, were selectively deficient in MS patients. To examine functional consequences of the lower SHP-1 in PBMCs of MS patients, we measured the intracellular levels of phosphorylated STAT6 (pSTAT6). As expected, MS patients had significantly higher levels of pSTAT6. Accordingly, siRNA to SHP-1 effectively increased the levels of pSTAT6 in PBMCs of controls to levels equal to MS patients. Additionally, transduction of PBMCs with a lentiviral vector expressing SHP-1 lowered pSTAT6 levels. Finally, multiple STAT6-responsive inflammatory genes were increased in PBMCs of MS patients relative to PBMCs of normal subjects. Thus, PBMCs of MS patients display a stable deficiency of SHP-1 expression, heightened STAT6 phosphorylation, and an enhanced state of activation relevant to the mechanisms of inflammatory demyelination.

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Regulation of avoidant behaviors and pain by the anti-inflammatory tyrosine phosphatase SHP-1

Cited by 8 publications

References 40 publications

Interferon-β treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1

Interferon-β treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1

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

SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients

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