WITH increasing frequency, the human neutrophil is being implicated as a mediator of tissue-destructive events in inflammatory diseases ranging from rheumatoid arthritis and myocardial reperfusion injury to respiratory distress syndromes, blistering skin disorders, and ulcerative colitis.1 , 2 In each of these diseases, as well as a variety of other acute inflammatory disorders, important components of these pathologic processes are being linked to the neutrophil's ability to release a complex assortment of agents that can destroy normal cells and dissolve connective tissues. Although these toxins normally defend the host against invading microbes, the neutrophil has little intrinsic ability to differentiate between foreign . . .

Tissue Destruction by Neutrophils

/pdf/purification-and-characterization-2y44lhntkf.pdf

Purification and Characterization

The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.

/pdf/principles-of-interleukin-il-6-type-cytokine-signalling-and-1tgjc4ttsu.pdf

Principles of interleukin (IL)-6-type cytokine signalling and its regulation.

Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Matrix Metalloproteinases: A Review

▪ Abstract Recent studies showing that detergent-resistant membrane fragments can be isolated from cells suggest that biological membranes are not always in a liquid-crystalline phase. Instead, sph...

Functions of lipid rafts in biological membranes.

PERSPECTIVES AND SUMMARy 655 INTRODUCTION 657 MECHANISM OF ACTION OF PROTEINASE INHIBITORS 659 The Standard Mechanism 660 Deviations Jrom the Standard M echanism 661 ALPHA I-PROTEINASE INHIBITOR 663 Polymorphysm oj (x, Proteinase Inhibitor 665 Mechanism Studies 667 Physiological Role of (x, Proteinase Inhibitor 672 ANTITHROMBIN III ...... 674 Effect oj Heparin 674 Mechanism Studies 675 Physiological Role of Antithrombin III 676 ALPHAz-ANTIPLASMIN 676 ALPHA,-ANTICHYMOTRYPSIN 678 CI-INHIBITOR 681 ALPHA2-MACROGLOBULIN 684 The Trapping Reaction ..... 685 The Covalent-Linking Reaction 690 The Adherence Reaction 693 Physiological Role oJ(Xz-Macroglobulin 693 INTER-ALPHA-TRYPSIN INHIBITOR 695 BETA,-ANTICOLLAGENASE 696 ALPHA-CYSTEINE PROTEINASE INHIBITOR 698 OTHER INHIBITORS 699 CONCLUDING REMARKS 700

Human plasma proteinase inhibitors

http://www.jbc.org/content/early/2001/07/02/jbc.R100016200.full.pdf

The serpins are an expanding superfamily of structurally similar but functionally diverse proteins - Evolution, mechanism of inhibition, novel functions, and a revised nomenclature

The serpin superfamily of proteinase inhibitors: structure, function, and regulation.

Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin.

Human granulocytic elastases have been purified by a two-step procedure involving affinity chromatography of crude extracts of leukocytic granules on Sepharose-Trasylol, followed by ion-exchange chromatography on CM-cellulose to resolve the isoelastases. All of these enzymes were found to be glycoproteins with the carbohydrate content of the major form being composed essentially of only neutral sugars. The molecular weight of this form was found to be near 30 000 daltons with the other forms being slightly higher. Preliminary structural analyses indicate that all of the elastase isozymes have identical NH2-terminal sequences suggesting that the differences in mobility of the four proteins are not due to different degrees of activation from a common zymogen but, more likely, from minor changes in carbohydrate content. Human granulocytic elastases are less active on ligament elastin than porcine pancreatic elastase, but both are inhibited by synthetic elastase active-site directed low molecular weight compounds (Tuhy, P. M., and Powers, J. C. (1975), FEBS Lett. 50, 359) as well as by plasma alpha-1-proteinase inhibitor (formerly called alpha-1-antitrypsin). In the latter case a stable complex with mol wt of 78 000 daltons is formed indicating the formation of a 1:1 complex.

James Travis

Papers

Human plasma proteinase inhibitors

The serpins are an expanding superfamily of structurally similar but functionally diverse proteins - Evolution, mechanism of inhibition, novel functions, and a revised nomenclature

The serpin superfamily of proteinase inhibitors: structure, function, and regulation.

Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin.

Human leukocyte granule elastase: rapid isolation and characterization