Advances in tenascin-C biology

Tenascin-C is an extracellular matrix glycoprotein that is specifically and transiently expressed upon tissue injury. Upon tissue damage, tenascin-C plays a multitude of different roles that mediate both inflammatory and fibrotic processes to enable effective tissue repair. In the last decade, emerging evidence has demonstrated a vital role for tenascin-C in cardiac and arterial injury, tumor angiogenesis and metastasis, as well as in modulating stem cell behavior. Here we highlight the molecular mechanisms by which tenascin-C mediates these effects and discuss the implications of mis-regulated tenascin-C expression in driving disease pathology.     

Fluctuation and response in biology

In 1905, Albert Einstein proposed that the forces that cause the random Brownian motion of a particle also underlie the resistance to macroscopic motion when a force is applied. This insight, of a coupling between fluctuation (stochastic behavior) and responsiveness (non-stochastic behavior), founded an important branch of physics. Here we argue that his insight may also be relevant for understanding evolved biological systems, and we present a ‘fluctuation–response relationship’ for biology. The relationship is consistent with the idea that biological systems are similarly canalized to stochastic, environmental, and genetic perturbations. It is also supported by in silico evolution experiments, and by the observation that ‘noisy’ gene expression is often both more responsive and more ‘evolvable’. More generally, we argue that in biology there is (and always has been) an important role for macroscopic theory that considers the general behavior of systems without concern for their intimate molecular details.     

Photon emission in tumor biology

Photon emission from mammalian cells has been subject of study for many years. Growing research activity is directed on the photon emission within the field of tumor biology. These studies, applying high-sensitivity photon counting methods, have paid attention to several aspects, including photon emission from serum of tumor-bearing animals, photon emission of tumors and of isolated tumor cells. In addition, research activity is increased with respect to the photon emission by white light from cultured tumor cells. In this review we report on the different aspects of spontaneous and induced photon emission of tumor cells as compared to normal cells. Throughout these studies the question of a functional biological role of this spontaneous and light-induced photon emission has been raised and some different points of view will be discussed.     

Regulation of macrophage activation

IFN- rapidly primes the macrophage via JAK1/2-STAT1 pathway so that it can subsequently undergo a slower classical type 1 activation upon exposure to T helper (Th)1 cytokines such as IFN or other activators, including tumor necrosis factor and lipopolysaccharide, e.g. in intracellular killing of phagocytosed Mycobacterium tuberculosis. If instead it is driven by Th2 cytokines interleukin (IL)-4 and IL-13, it undergoes alternate type 2 activation, which enhances endocytotic antigen uptake and presentation, mast cell and eosinophil involvement and type 2 granuloma formation, e.g. in response to parasitic and extracellular pathogens. Particle-induced macrophage activation was shown to differ from classical and alternate activation, showing in DNA microarray experiments (complete linkage/ Euclidean distance metric analysis) upregulation of nonsecreted structural/signaling molecules and lack of secreted proin-flammatory cyto- and chemokines. The switch-off (deactivation) of already activated macrophages is an active, controlled process in which IL-10 and corticosteroids play important roles and to which15dPGJ2, PGA1/2 and vasoactive intestinal peptide often contribute.Received 16 January 2003; received after revision 14 March 2003; accepted 2 April 2003     

Specificity of the macrophage reaction in vitro

Résumé Les macrophages de cobayes immunisés provoquent in vitro l'adhérence des hématies utilisées comme antigènes, selon une spécificité d'éspèce et non de groupe. Les sérums humains s'adsorbent in vitro sur les macrophages de cobayes immunisés par ces sérums, indépendemment du groupe (mais non sur des macrophages de cobayes normaux) causant l'adhérence et la phagocytose des hématies correspondantes. Les hématies adhérant aux macrophages sont hémolysées en présence du complément.     

Histone-induced macrophage disappearance reaction in normal guinea-pigs

Zusammenfassung Histon aus Kalbsthymus bewirkt nach i.p. oder s.c. Injektion bei nichtimmunisierten Meerschweinchen in gleicher Weise eine ausgeprägte Abnahme von Makrophagen in einem mit Glykogen induzierten Peritonealexsudat wie eine Injektion von Antigen bei spätallergischen Tieren. Eine Histonbehandlung während einer Immunisierung mit BCG unterdrückt die sonst mit Tuberkulin auslösbare sogenannte «macrophage disappearance reaction».     

Normal macrophage migration inhibition in dexamethasone-treated guinea-pigs

Résumé L'inhibition de la migration des macrophages se voit chez les cobayes immunisés à la tuberculine, même au cours d'un traitement in vivo au dexaméthasone. In vitro le dexaméthasone abolit cette inhibition de même que la réponse au facteur inhibitif de la migration des cellules des cobayes témoins.

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Supported by grants from The Arthritis Foundation and The New York Chapter of the Arthritis Foundation.     

Photon emission in tumor biology.

Photon emission from mammalian cells has been subject of study for many years. Growing research activity is directed on the photon emission within the field of tumor biology. These studies, applying high-sensitivity photon counting methods, have paid attention to several aspects, including photon emission from serum of tumor-bearing animals, photon emission of tumors and of isolated tumor cells. In addition, research activity is increased with respect to the photon emission induced by white light from cultured tumor cells. In this review we report on the different aspects of spontaneous and induced photon emission of tumor cells as compared to normal cells. Throughout these studies the question of a functional biological role of this spontaneous and light-induced photon emission has been raised and some different points of view will be discussed.     

PTEN proteoforms in biology and disease

Proteoforms are specific molecular forms of protein products arising from a single gene that possess different structures and different functions. Therefore, a single gene can produce a large repertoire of proteoforms by means of allelic variations (mutations, indels, SNPs), alternative splicing and other pre-translational mechanisms, post-translational modifications (PTMs), conformational dynamics, and functioning. Resulting proteoforms that have different sizes, alternative splicing patterns, sets of post-translational modifications, protein–protein interactions, and protein–ligand interactions, might dramatically increase the functionality of the encoded protein. Herein, we have interrogated the tumor suppressor PTEN for its proteoforms and find that this protein exists in multiple forms with distinct functions and sub-cellular localizations. Furthermore, the levels of each PTEN proteoform in a given cell may affect its biological function. Indeed, the paradigm of the continuum model of tumor suppression by PTEN can be better explained by the presence of a continuum of PTEN proteoforms, diversity, and levels of which are associated with pathological outcomes than simply by the different roles of mutations in the PTEN gene. Consequently, understanding the mechanisms underlying the dysregulation of PTEN proteoforms by several genomic and non-genomic mechanisms in cancer and other diseases is imperative. We have identified different PTEN proteoforms, which control various aspects of cellular function and grouped them into three categories of intrinsic, function-induced, and inducible proteoforms. A special emphasis is given to the inducible PTEN proteoforms that are produced due to alternative translational initiation. The novel finding that PTEN forms dimers with biological implications supports the notion that PTEN proteoform–proteoform interactions may play hitherto unknown roles in cellular homeostasis and in pathogenic settings, including cancer. These PTEN proteoforms with unique properties and functionalities offer potential novel therapeutic opportunities in the treatment of various cancers and other diseases.     

Thrombin-induced ‘macrophage disappearance reaction’ in mice

Zusammenfassung Intraperitoneale Gabe von Thrombin verursachte ein praktisch völliges Verschwinden der Makrophagen aus der Peritonealflüssigkeit, beeinflusste aber kaum die Zahl der Lymphozyten.

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The authors thank Mr.A. Zsigmondy for his expert technical assistance.     

Heterogeneity of macrophage cytophilic antibodies in immunized mice

Résumé Des souris immunisés avec des globules rouges de mouton dans l'adjuvant de Freund produisent deux types de facteurs cytophiles pour macrophages. L'un s'attache aux macrophages trypsinisées et se trouve parmi les immunoglobulines. L'autre ne s'attache pas aux macrophages trypsinisées et se rencontre dans une fraction de sérum contenant de l'albumine et de la globuline-₁.

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Supported by grants from the Australian Research Grants Committee, the National Health and Medical Research Council of Australia and the Postgraduate Medical Foundation, University of Sydney.     

Biochemistry of proinflammatory macrophage activation

In the last decade, metabolism has been recognized as a major determinant of immunological processes. During an inflammatory response, macrophages undergo striking changes in their metabolism. This metabolic reprogramming is governed by a complex interplay between metabolic enzymes and metabolites of different pathways and represents the basis for proper macrophage function. It is now evident that these changes go far beyond the well-known Warburg effect and the perturbation of metabolic targets is being investigated as a means to treat infections and auto-immune diseases. In the present review, we will aim to provide an overview of the metabolic responses during proinflammatory macrophage activation and show how these changes modulate the immune response.     

Massive glycosaminoglycan-dependent entry of Trp-containing cell-penetrating peptides induced by exogenous sphingomyelinase or cholesterol depletion

Among non-invasive cell delivery strategies, cell-penetrating peptide (CPP) vectors represent interesting new tools. To get fundamental knowledge about the still debated internalisation mechanisms of these peptides, we modified the membrane content of cells, typically by hydrolysis of sphingomyelin or depletion of cholesterol from the membrane outer leaflet. We quantified and visualised the effect of these viable cell surface treatments on the internalisation efficiency of different CPPs, among which the most studied Tat, R₉, penetratin and analogues, that all carry the N-terminal biotin-Gly₄ tag cargo. Under these cell membrane treatments, only penetratin and R₆W₃ underwent a massive glycosaminoglycan (GAG)-dependent entry in cells. Internalisation of the other peptides was only slightly increased, similarly in the absence or the presence of GAGs for R₉, and only in the presence of GAGs for Tat and R₆L₃. Ceramide formation (or cholesterol depletion) is known to lead to the reorganisation of membrane lipid domains into larger platforms, which can serve as a trap and cluster receptors. These results show that GAG clustering, enhanced by formation of ceramide, is efficiently exploited by penetratin and R₆W₃, which contains Trp residues in their sequence but not Tat, R₉ and R₆L₃. Hence, these data shed new lights on the differences in the internalisation mechanism and pathway of these peptides that are widely used in delivery of cargo molecules.