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1.  TGF-β promotes Th17 cell development through inhibition of SOCS3 
TGF-β, together with IL-6 and IL-21, promotes Th17 cell development. IL-6 and IL-21 induce activation of STAT3, which is crucial for Th17 cell differentiation, as well as the expression of SOCS3, a major negative feedback regulator of STAT3-activating cytokines that negatively regulates Th17 cells. However, it is still largely unclear how TGF-β regulates Th17 cell development, and which TGF-β signaling pathway is involved in Th17 cell development. In this report, we demonstrate that TGF-β inhibits IL-6- and IL-21-induced SOCS3 expression, thus enhancing as well as prolonging STAT3 activation in naïve CD4+CD25− T cells. TGF-β inhibits IL-6-induced SOCS3 promoter activity in T cells. Also, SOCS3 siRNA knockdown partially compensates for the action of TGF-β on Th17 cell development. In mice with a dominant-negative form of TGF-β receptor II (TGF-β RII DN) and impaired TGF-β signaling, IL-6-induced CD4+ T cell expression of SOCS3 is higher, whereas STAT3 activation is lower compared to wild type B6 CD4+ T cells. Addition of a TGF-β RI kinase inhibitor that blocks Smad-dependent TGF-β signaling greatly, but not completely, abrogates the effect of TGF-β on Th17 cell differentiation. Our data indicate that inhibition of SOCS3 and thus enhancement of STAT3 activation is at least one of the mechanisms of TGF-β promotion of Th17 cell development.
PMCID: PMC2851540  PMID: 19535626
2.  Expression and Functional Significance of SOCS-1 and SOCS-3 in Astrocytes 
Astrocytes play a number of important physiological roles in Central Nervous System (CNS) homeostasis. Inflammation stimulates astrocytes to secrete cytokines and chemokines that guide macrophages/microglia and T-cells to sites of injury/inflammation, and herein we describe how these processes are controlled by the Suppressor Of Cytokine Signaling (SOCS) proteins, a family of proteins that negatively regulate adaptive and innate immune responses. In this study, we describe that the immunomodulatory cytokine IFN-β induces SOCS-1 and SOCS-3 expression in primary astrocytes at the transcriptional level. SOCS-1 and SOCS-3 transcriptional activity is induced by IFN-β through GAS elements within their promoters. Studies in STAT-1α deficient astrocytes indicate that STAT-1α is required for IFN-β-induced SOCS-1 expression, while STAT-3 siRNA studies demonstrate that IFN-β-induced SOCS-3 expression relies on STAT-3 activation. Specific siRNA inhibition of IFN-β-inducible SOCS-1 and SOCS-3 in astrocytes enhances their pro-inflammatory responses to IFN-β stimulation, such as heightened expression of the chemokines CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES) and CXCL10 (IP-10), and promoting chemotaxis of macrophages and CD4+ T-cells. These results indicate that IFN-β induces SOCS-1 and SOCS-3 in primary astrocytes in order to attenuate its own chemokine-related inflammation in the CNS.
PMCID: PMC2836124  PMID: 18713987
3.  Allele frequencies of hemojuvelin gene (HJV) I222N and G320V missense mutations in white and African American subjects from the general Alabama population 
BMC Medical Genetics  2004;5:29.
Homozygosity or compound heterozygosity for coding region mutations of the hemojuvelin gene (HJV) in whites is a cause of early age-of-onset iron overload (juvenile hemochromatosis), and of hemochromatosis phenotypes in some young or middle-aged adults. HJV coding region mutations have also been identified recently in African American primary iron overload and control subjects. Primary iron overload unexplained by typical hemochromatosis-associated HFE genotypes is common in white and black adults in Alabama, and HJV I222N and G320V were detected in a white Alabama juvenile hemochromatosis index patient. Thus, we estimated the frequency of the HJV missense mutations I222N and G320V in adult whites and African Americans from Alabama general population convenience samples.
We evaluated the genomic DNA of 241 Alabama white and 124 African American adults who reported no history of hemochromatosis or iron overload to detect HJV missense mutations I222N and G320V using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Analysis for HJV I222N was performed in 240 whites and 124 African Americans. Analysis for HJV G320V was performed in 241 whites and 118 African Americans.
One of 240 white control subjects was heterozygous for HJV I222N; she was also heterozygous for HFE C282Y, but had normal serum iron measures and bone marrow iron stores. HJV I222N was not detected in 124 African American subjects. HJV G320V was not detected in 241 white or 118 African American subjects.
HJV I222N and G320V are probably uncommon causes or modifiers of primary iron overload in adult whites and African Americans in Alabama. Double heterozygosity for HJV I222N and HFE C282Y may not promote increased iron absorption.
PMCID: PMC544351  PMID: 15610558

Results 1-3 (3)