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Background: The aim of this study was to investigate the role of matrix metalloproteinase-9 ( MMP-9) C-1562T and 279R/Q (836G>A) polymorphisms in the development of chronic obstructive pulmonary disease (COPD) in Tunisians and to determine their impact on disease progression and airflow obstruction. Methods: Pulmonary functional tests were evaluated by body plethysmography. MMP-9 genotypes were determined in patients with COPD ( n = 138) and healthy controls ( n = 216) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum MMP-9 and interleukin-6 (IL-6) levels were determined by enzyme-linked immunosorbent assays (ELISA) and activity of MMP-9 was evaluated by gelatin zymography. Results: No significant association was found between genetic variations in MMP-9 C-1562T and 279R/Q polymorphisms and the risk of development of COPD. However, a significant correlation was retrieved between the 279 R/Q polymorphism and disease severity ( P = 0.02). In addition, homozygous Q (A) genotype was associated with a poorer lung function with a fall in forced expiratory volume in 1 s (FEV) (%) and forced vital capacity (FVC%) among COPD patients compared with both AG and GG individuals (52.06 ± 19.6 vs. 59.08 ± 17.19, P = 0.03 and 72.41 ± 21.42 vs. 82.98 ± 16.48, P = 0.002, respectively). Using ELISA, a higher level of MMP-9 was found in patients with the CT genotype ( P = 0.03), while no significant impact of the 279R/Q polymorphism was observed ( P = 0.48). In contrast, by using zymography gel analysis, MMP-9 activity was enhanced in individuals carrying the R(G) allele in comparison with those homozygous for the Q(A) variant ( P = 0.02). Conclusion: Our results support a role for the 279R/Q polymorphism in physiological alterations that may affect progression and severity of COPD. These findings could be related to the decreased activity of MMP-9 among COPD patients carrying the 279Q variant. [ABSTRACT FROM AUTHOR]

Transmembrane proteases (TPs) are proteins anchored in the plasma membrane with their catalytic site exposed to the external surface of the membrane. TPs are widely expressed, and their dysregulated expression is associated with cancer, infection, inflammation, autoimmune and cardiovascular diseases, all diseases where angiogenesis is part of the pathology. TPs participate in extracellular proteolysis (degradation of extracellular matrix components, regulation of chemokine activity, release of membrane-anchored cytokines, cytokine receptors and adhesion molecules) and influence cell functions (growth, secretion of angiogenic molecules, motility). Recent attention has been focused on the ADAM-17 (a disintegrin and metalloprotease)/TACE/CD156q, the MT1-MMP (membrane-type-1 matrix metallo proteinase)/MMP-14, and the ectopeptidases aminopeptidase N (APN/CD13), dipeptidyl peptidase IV (DPPIV/CD26) and angiotensin-converting enzyme (ACE/CD143), that appear to have a critical role in angiogenesis. This article summarizes current knowledge on these TPs, and reviews recent investigations that document their participation during angiogenic-related events. Through their multiple roles, TPs may thereby provide critical links in angiogenesis.Oncogene (2004) 23, 317-329. doi:10.1038/sj.onc.1207124 [ABSTRACT FROM AUTHOR]

Interferons (IFNs α, β and γ) and all trans retinoic acid (RA) have the ability to activate genes with GAS sites. We have found that the promoter of CD26/dipeptidylpeptidase IV (DPPIV) contains a consensus GAS site TTCnnnGAA located at bp-35 to -27, and computer analysis confirmed this sequence to be a putative Stat binding site. Consistent with this finding, we show that IFNs and RA rapidly enhanced CD26 gene and protein expression in chronic B lymphocytic leukemia (B-CLL) cells. Immunoblot analyses revealed that unstimulated B-CLL cells expressed detectable levels of serine/tyrosine-phosphorylated Stat1α, and RA and IFN-γ treatment led to increased levels of tyrosine phosphorylation of Stat1α and its nuclear accumulation. As shown by electrophoretic mobility shift assay, RA and IFN-γ increased the binding of a nuclear protein to the GAS-CD26 element. Shift-Western blotting identified Stat1α as the GAS-CD26 binding factor. Augmented levels of CD26 protein in malignant B cells cultured with IFNs or RA coincided with the enhancement of DPPIV activity. Taken together, our results are in favor of the IFN-/RA-mediated upregulation of CD26/DPPIV in B-CLL through the signaling pathway involving Stat1α and the GAS response element of CD26 promoter.Oncogene (2000) 19, 265–272 [ABSTRACT FROM AUTHOR]

Introduction: Modulation of the adhesive responses of monocytic cells may reflect their motility within the bone marrow and at sites of inflammation. Monocyte α5β1 integrins mediate fibronectin-dependent adhesion. We previously showed that type II IFN-γ reduces adhesiveness to fibronectin (Fn) whereas TGF-β1 enhances cell attachment. Here, we investigate the role of type I IFNs (α, β) on the adhesive capacity of monocytic cells. Materials and methods: The influence of IFNs on the human U937 cell line adhesion to fibronectin-coated surfaces was determined. The expression of integrins and cytoskeleton proteins was analyzed by FACS, Western blotting and/or fluorescence microscopy analyses. Results: IFN-α did not affect cell adhesion to fibronectin. In contrast, IFN-β, like IFN-γ, abrogated U937 adhesion to fibronectin and antagonized TGF-β1-mediated cell attachment to Fn. The impaired binding of IFN-β- and IFN-γ-treated cells to fibronectin was not due to reduced levels of α5β1 integrins. IFN-β and IFN-γ re-organized filamentous actin, and such rearrangement differed from that observed in TGF-β1-adhesive cells. U937 cells dominantly expressed 44 to 46 kDa paxillin forms and treatment with IFNs enhanced the number of 66 to 70 kDa forms of paxillin. Conclusion: Our data show that IFN-β and IFN-γ induced loss of monocytic adhesion to fibronectin associated with changes in actin and paxillin cytoskeleton, thereby pointing to a possible effect of these cytokines in monocyte trafficking. [ABSTRACT FROM AUTHOR]