J. Van Damme

The role of chemokines in inflammation

Chemokines, together with adhesion molecules, cytokines, and proteases, are essential for the directional migration of leukocytes during normal and inflammatory processes. Interleukin-8 and monocyte chemotactic protein-1 are the best-characterized members of the C-X-C and C-C chemokine subfamilies, respectively. However, more than 20 human chemokines have been identified but are only partially characterized at the biological level. Chemokines are involved in chemotaxis of monocytes, lymphocytes, neutrophils, eosinophils, basophils, natural killer cells, dendritic cells, and endothelial cells. This review describes the chemokine subfamilies, the chemokine producer and target cells, their receptors, singal transduction mechanisms, and the role of chemokines during physiological and pathological conditions. More and more evidence points to a role for chemokines in chemotaxis-related phenomena, such as the expression of adhesion molecules, the secretion of proteinases, inhibition of apoptosis, hematopoiesis, and angiogenesis. Chemokines are also involved in diseases such as cancer (tumor regression and tumor metastasis), autoimmune diseases, and bacterial or viral infection.

Lom-AG-myotropin: A novel myotropic peptide from the male accessory glands of Locusta migratoria

A myotropic peptide, termed Lom-AG-myotropin, was isolated from extracts of 4400 accessory gland complexes of males of the locust, Locusta migratoria; the following sequence was derived: Gly-Phe-Lys-Asn-Val-Ala-Leu-Ser-Thr-Ala-Arg-Gly-Phe-NH2. This sequence is completely different from all presently known myotropic peptides from Locusta or other insects. The Lom-AG-myotropin is active on the oviduct and hindgut of Locusta migratoria and Leucophaea maderae. The stimulatory activity is, in both insects, 1000 times greater on the oviduct than on the hindgut, suggesting a specificity for the oviduct.

Chemokines: A superfamily of chemotactic cytokines

Chemokines are a bipartite family of chemotactic proteins that bear the structural hallmark of four cysteine residues, the first two of which are in tandem. The spectrum of action of chemokines encompasses a large number of leukocyte populations, including monocytes, granulocytes, lymphocytes, NK and dendritic cells. Although the spectrum of action of chemokines largely overlaps, clear differences are still present. Chemokines play an important role in the recruitment of leukocytes at the site of inflammation, allergic reaction and tumors. Available information on receptor usage by MCP-1 and related chemokines and signal transduction pathways is reviewed. The better understanding of signaling mechanisms will provide a new basis for the development of therapeutic strategies.

Amino-terminal Truncation of Chemokines by CD26/Dipeptidyl- peptidase IV

Chemokines are key players in inflammation and infection. Natural forms of the C-X-C chemokine granulocyte chemotactic protein-2 (GCP-2) and the C-C chemokine regulated on activation normal T cell expressed and secreted (RANTES), which miss two NH2-terminal residues, including a Pro in the penultimate position, have been isolated from leukocytes or tumor cells. In chemotaxis and intracellular calcium mobilization assays, the truncation caused a reduction in the specific activity of RANTES but not of GCP-2. The serine protease CD26/dipeptidyl-peptidase IV (CD26/DPP IV) could induce this observed NH2-terminal truncation of GCP-2 and RANTES but not that of the monocyte chemotactic proteins MCP-1, MCP-2 and MCP-3. No significant difference in neutrophil activation was detected between intact and CD26/DPP IV-truncated GCP-2. In contrast to intact natural RANTES(1–68), which still chemoattracts monocytes at 10 ng/ml, CD26/DPP IV-truncated RANTES(3–68) was inactive at 300 ng/ml and behaved as a natural chemotaxis inhibitor. Compared with intact RANTES, only a 10-fold higher concentration of RANTES(3–68) induced a significant Ca2+ response. Furthermore, RANTES(3–68) inhibited infection of mononuclear cells by an M-tropic HIV-1 strain 5-fold more efficiently than intact RANTES. Thus, proteolytic processing of RANTES by CD26/DPP IV may constitute an important regulatory mechanism during anti-inflammatory and antiviral responses.

Leukocyte migration and activation by murine chemokines.

Chemokines are a family of chemotactic cytokines which attract different types of leukocytes. This property, combined with some additional inflammatory and growth-regulatory activities, demonstrate their crucial role in the immune system. Chemokines are low molecular weight proteins and possess a typical positioning of four conserved cysteines. This family is further subdivided in two subfamilies depending on whether the first two cysteines are adjacent or not (CC and CXC chemokines, respectively). The CXC chemokines (including interleukin-8) predominantly attract neutrophils, whereas CC chemokines induce migration of monocytes, as well as other leukocyte cell types. In this article, the general characteristics of chemokines are reviewed. Furthermore, the murine CC chemokines, JE/MCP-1, MCP-3/MARC, MIP-1 alpha, MIP-1 beta, RANTES, TCA3, C10/MRP-1, MRP-2, and eotaxin, are discussed more in detail.

Interleukin 1 preferentially stimulates the production of tissue-type plasminogen activator by human articular chondrocytes

Interleukin 1, derived from human placenta, stimulates plasminogen activator activity in human articular chondrocytes. The stimulation of plasminogen activator activity can be abolished by preincubation of placental interleukin 1 with an antiserum to homogeneous 22K factor, a species of interleukin 1 beta, indicating that the stimulation of plasminogen activator activity is due to interleukin 1 and not contaminating factors. Chondrocytes produce three species of plasminogen activator, with apparent Mr approximately 50,000, 65,000 and 100,000 as determined after sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis with gels containing casein and plasminogen. Both placental interleukin 1 and 22K factor enhance the production of the species of Mr approximately 65,000 and 100,000. Comparison of the mobility of the plasminogen activator species on SDS-polyacrylamide gel electrophoresis with human urokinase (u-PA) and human melanoma tissue-type plasminogen activator (t-PA) and studies with antibodies to these enzymes indicate that the Mr approximately 50,000 species is a u-PA and the Mr approximately 65,000 a t-PA. The Mr approximately 100,000 species is possibly an enzyme-inhibitor complex. Interleukin 1 therefore appears to enhance the production of t-PA and a putative enzyme-inhibitor complex. Abolition of plasminogen activator activity in the fibrin plate assay with antibodies to t-PA and u-PA also confirms enhanced t-PA production on interleukin 1 stimulation, though there is also evidence for increased cell-associated production of u-PA.

TNF-α and the IFN-γ-inducible protein 10 (IP-10/CXCL-10) delivered by parvoviral vectors act in synergy to induce antitumor effects in mouse glioblastoma

Interferon-γ-inducible protein 10 is a potent chemoattractant for natural killer cells and activated T lymphocytes. It also displays angiostatic properties and some antitumor activity. Tumor necrosis factor-α (TNF-α) is a powerful immunomodulating cytokine with demonstrated tumoricidal activity in various tumor models and the ability to induce strong immune responses. This prompted us to evaluate the antitumor effects of recombinant parvoviruses designed to deliver IP-10 or TNF-α into a glioblastoma. When Gl261 murine glioma cells were infected in vitro with an IP-10- or TNF-α-transducing parvoviral vector and were subcutaneously implanted in mice, tumor growth was significantly delayed. Complete tumor regression was observed when the glioma cells were coinfected with both the vectors, demonstrating synergistic antitumor activity. In an established in vivo glioma model, however, repeated simultaneous peritumoral injection of the IP-10- and TNF-α-delivering parvoviruses failed to improve the therapeutic effect as compared with the use of a single cytokine-delivering vector. In this tumor model, cytokine-mediated immunostimulation, rather than inhibition of vascularization, is likely responsible for the therapeutic efficacy.

Cells regulate the activities of cytokines by glycosylation.

Cytokines, including the interferons, interleukins, colony stimulating factors, and chemokines, are first‐line, hormone‐like defense molecules that orchestrate immune functions in a nonspecific, i.e., antigen‐independent, way. The multiplicity of cytokines has a genetic basis, but oligomerization and especially glycosylation add to the heterogeneity and signaling functions of the cytokines. It is theorized that the cell uses glycosylation of cytokines to alter its functions. This is achieved by changing the specific biological activities, by altering diffusability, tissue distribution, and pharmacokinetics, and by targeting different populations of responsive cells. One interesting possibility is that multiple glycosylation forms compete for receptor binding resulting in a natural selection process or possibly antagonistic effects. Cytokines as ligands often are multimers and cytokine receptors are almost without exception heterodimers, which within receptor families share common subunits. Hence, carbohydrate‐lectin interactions might contribute to ligand dimerization and receptor recognition through multivalent bindings.—Opdenakker, G., Rudd, P. M., Wormald, M., Dwek, R. A., Van Damme, J. Cells regulate the activities of cytokines by glycosylation. FASEB J. 9, 453–457 (1995)

Transduction of human MCP-3 by a parvoviral vector induces leukocyte infiltration and reduces growth of human cervical carcinoma cell xenografts

The oncosuppressive properties of some autonomous parvoviruses such as H‐1 virus, together with their low pathogenicity, make them attractive vectors for tumor‐directed gene therapy. Indeed, it was recently shown that these viruses became endowed with an enhanced oncosuppressive activity after they had been engineered to deliver a recognized therapeutic transgene. This prompted us to use a parvoviral vector to analyse the antineoplastic capacity of MCP‐3 (monocyte chemotactic protein‐3), a CC chemokine which has a broad spectrum of target cells, and can thus be considered to be a promising candidate for cancer treatment.

Interleukin-6 and coagulation-fibrinolysis fluctuations after laparoscopic and conventional cholecystectomy

This study assesses quantitatively the fluctuations of interleukin-6 (IL-6) and coagulationfibrinolysis proteins in patients undergoing elective laparoscopic (n=14) and conventional (n=10) cholecystectomy. The patients in both groups were comparable in age and sex. Serum levels of interleukin-6, and plasma levels of fibrinogen, von Willebrand factor-antigen, tissue-type plasminogen activator-antigen, and plasminogen activator inhibitor-1 were determined for up to 48 h postoperatively. The postoperative changes of all parameters tested were comparable in both patient groups with a trend toward a higher interleukin-6 response at 8 h postincision (NS) and a trend toward a higher fibrinolysis inhibition (NS) after conventional cholecystectomy.