IFN-γ, IL-4 and IL-13 modulate responsiveness of human airway smooth muscle cells to IL-13

© 2008 Moynihan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Alternate Splicing of Interleukin-1 Receptor Type II (IL1R2) In Vitro Correlates with Clinical Glucocorticoid Responsiveness in Patients with AIED

Autoimmune Inner Ear Disease (AIED) is poorly characterized clinically, with no definitive laboratory test. All patients suspected of having AIED are given glucocorticoids during periods of acute hearing loss, however, only half initially respond, and still fewer respond over time

Induction of interferon-stimulated genes on the IL-4 response axis by Epstein-Barr virus infected human b cells; relevance to cellular transformation.

Epstein-Barr virus (EBV) is an oncogenic virus that is associated with the pathogenesis of several human lymphoid malignancies, including Hodgkin's lymphoma. Infection of normal resting B cells with EBV results in activation to lymphoblasts that are phenotypically similar to those generated by physiological stimulation with CD40L plus IL-4. One important difference is that infection leads to the establishment of permanently growing lymphoblastoid cell lines, whereas CD40L/IL-4 blasts have finite proliferation lifespans. To identify early events which might later determine why EBV infected blasts go on to establish transformed cell lines, we performed global transcriptome analyses on resting B cells and on EBV and CD40L/IL-4 blasts after 7 days culture. As anticipated there was considerable overlap in the transcriptomes of the two types of lymphoblasts when compared to the original resting B cells, reflecting common changes associated with lymphocyte activation and proliferation. Of interest to us was a subset of 255 genes that were differentially expressed between EBV and CD40L/IL-4 blasts. Genes which were more highly expressed in EBV blasts were substantially and significantly enriched for a set of interferon-stimulated genes which on further in silico analyses were found to be repressed by IL-4 in other cell contexts and to be up-regulated in micro-dissected malignant cells from Hodgkin's lymphoma biopsies when compared to their normal germinal center cell counterparts. We hypothesized that EBV and IL-4 were targeting and discordantly regulating a common set of genes. This was supported experimentally in our B cell model where IL-4 stimulation partially reversed transcriptional changes which follow EBV infection and it impaired the efficiency of EBV-induced B cell transformation. Taken together, these data suggest that the discordant regulation of interferon and IL-4 pathway genes by EBV that occurs early following infection of B cells has relevance to the development or maintenance of an EBV-associated malignancy

Kinetics of serum soluble tumour necrosis factor receptor (TNF-R) type-I and type-II after a single interferon-alpha (IFN-α) injection in chronic hepatitis C

Circulating soluble TNF receptors, which act as TNF inhibitors, increase following the administration of IFN-α. Whether this is due to a direct IFN action or to indirect mechanisms involving the release of other cytokines is unclear. The kinetics of serum IFN, TNF, IL-6, IL-10, soluble TNF receptor type-I (sTNF-RI) and sTNF-RII were evaluated by enzyme immunoassays in 11 patients with chronic hepatitis C, following the first dose of recombinant human IFN-α2b (3 MU given subcutaneously). sTNF-RI concentrations paralleled IFN concentrations, rising from a mean ± s.e.m. value of 3.5 ± 0.3 ng/ml at baseline to a peak value of 5.5 ± 0.5 ng/ml after 9 h, followed by a return to 4.1 ± 0.4 ng/ml after 24 h (P = 0.0001). sTNF-RII concentrations, which were 7.6 ± 0.5 ng/ml at baseline, fell initially to 6.9 ± 0.5 ng/ml, to reach a peak at 24 h of 9.0 ± 0.7 ng/ml (P < 0.0001). In contrast, the concentrations of TNF, IL-6 and IL-10 fluctuated with no significant changes at any time point. The area under the curve (AUC) of incremental IFN values had a strong positive correlation with the AUC of incremental sTNF-RI values (r = 0.75, P < 0.01). In patients with hepatitis C, IFN concentrations reached after a single dose of IFN were paralleled by correlationally increased concentrations of sTNF-RI, which are a much better marker of administered IFN than sTNF-RII, IL-6 or IL-10

DNA methylation and not allelic variation regulates STAT6 expression in human T cells

STAT6 transcription factor, which has been implicated in commitment to Th2, is known to be activated by IL-4 and IL-13. Accordingly, STAT6 is primarily responsible for the transcriptional effects of IL-4 and IL-13. STAT6-deficient mice are known to have defective IL-4-mediated functions, such as B cell proliferation, Th2 cell development and IgE secretion; therefore, they primarily contain the Th1 phenotype. However, the mechanism responsible for regulation of STAT6 expression transcriptionally and post-transcriptionally has yet to be elucidated. Here, we characterized the human STAT6 promoter gene and found that the transcriptional regulatory elements CCAAT and ATF were important for the STAT6 promoter activity. Direct sequencing analysis revealed that the 13 GT repeat allelic variation in noncoding exon 1 of the STAT6 gene appeared more frequently in 91 patients with asthma or rheumatoid arthritis than the 15 GT repeat variation, which is the dominant phenotype in healthy controls. However, it appears that this allelic variation did not affect the STAT6 transcriptional activity. Interestingly, treatment with a DNA methyltransferase inhibitor markedly increased the expression of STAT6 mRNA and protein in human primary T cells. In contrast, IFN-gamma treatment significantly repressed the STAT6 transcriptional activity. Therefore, the present study provides insight into the molecular basis of STAT6 expression, and in particular, demonstrates that STAT6 expression is associated with DNA hypermethylation rather than promoter polymorphisms or allelic variations.This work was supported by the Korea Science and Engineering Foundation (KOSEF) [R01-2007-000-20007-0, 2008)] and KOSEF through the Rheumatism Research Center (R11- 2002-098-05003, 2008) grants funded by the Korea government.Shin HJ, 2005, J IMMUNOL, V175, P7143Mowen KA, 2004, IMMUNOL REV, V202, P203Gao PS, 2004, J MED GENET, V41, P535, DOI 10.1136/jmg.2003.015842Fitzpatrick DR, 2003, CLIN IMMUNOL, V109, P37, DOI 10.1016/S1521-6616(03)00205-5Richardson B, 2003, CLIN IMMUNOL, V109, P72, DOI 10.1016/S1521-6616(03)00206-7Yano S, 2003, J IMMUNOL, V171, P2510Bruniquel D, 2003, NAT IMMUNOL, V4, P235, DOI 10.1039/ni887Jaenisch R, 2003, NAT GENET, V33, P245, DOI 10.1038/ng1089Elser B, 2002, IMMUNITY, V17, P703Chang HC, 2002, J IMMUNOL, V169, P4124White GP, 2002, J IMMUNOL, V168, P2820Farrar JD, 2002, J CLIN INVEST, V109, P431, DOI 10.1172/JC01200215093Mullings RE, 2001, J ALLERGY CLIN IMMUN, V108, P832Zhu JF, 2001, J IMMUNOL, V166, P7276Christodoulopoulos P, 2001, J ALLERGY CLIN IMMUN, V107, P586, DOI 10.1067/mai.2001.114883Rengarajan J, 2000, IMMUNOL TODAY, V21, P479Murphy KM, 2000, ANNU REV IMMUNOL, V18, P451Ouyang WJ, 2000, IMMUNITY, V12, P27Kurata H, 1999, IMMUNITY, V11, P677Kim JI, 1999, IMMUNITY, V10, P745Ferber IA, 1999, CLIN IMMUNOL, V91, P134Dickensheets HL, 1999, J LEUKOCYTE BIOL, V65, P307Georas SN, 1998, BLOOD, V92, P4529Ouyang W, 1998, IMMUNITY, V9, P745Mikovits JA, 1998, MOL CELL BIOL, V18, P5166Fitzpatrick DR, 1998, J EXP MED, V188, P103Akimoto T, 1998, J EXP MED, V187, P1537Kuperman D, 1998, J EXP MED, V187, P939Curiel RE, 1997, EUR J IMMUNOL, V27, P1982Kubo M, 1997, EMBO J, V16, P4007Xu J, 1997, BIOCHEM BIOPH RES CO, V235, P394Zheng WP, 1997, CELL, V89, P587Penix LA, 1996, J BIOL CHEM, V271, P31964Takeda K, 1996, NATURE, V380, P627Kaplan MH, 1996, IMMUNITY, V4, P313BACON CM, 1995, P NATL ACAD SCI USA, V92, P7307JACOBSON NG, 1995, J EXP MED, V181, P1755YOUNG HA, 1994, J IMMUNOL, V153, P3603