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.

The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals.

ACTH Acutephas specific receptors on different target cells leading to a Corsol proteins systemic reaction characterized by fever, leukocytosis, increase in erythrocyte sedimentation rate, increases in Leucocytosis secretion of ACTH and glucocorticoids, activation of Complement activat complement and clotting cascades, decreases in serum levels of iron and zinc, a negative nitrogen balance, and by dramatic changes in the concentration of some plasma ,l' proteins. These proteins are named acute phase proteins. i Acute phase proteins The acute phase protein patterns vary from one species to another. C-reactive protein and serum amyloid A, for example, show the highest increases during an acute phase response in man, whereas in the rat, a2-macroglobulin and al-acid glycoprotein are the acute phase proteins with the most spectacular changes (Table 1). In many species plasma levels of fibrinogen, haptoglobin, al-antichymotrypsin and a1-antitrypsin increase during an acute phase response [1-9]; simultaneously, albumin and transferrin concentrations decrease. These changes in plasma levels of acute phase proteins are preceded by corresponding alterations in mRNA concentrations. In addition, increases in the rates of secretion of some acute phase proteins have been observed. The earliest description of the acute phase response came from the ancient Greeks [10]. They already observed an increased sedimentation rate of erythrocytes in blood of severely ill patients. As we know today, this increase is due to elevated plasma concentrations of fibrinogen and other acute phase proteins [11]. The term 'acute

Interleukin-6 (IL-6), leukemia inhibitory factor, oncostatin M, interleukin-11, and ciliary neurotrophic factor bind to receptor complexes that share the signal transducer gp130. Upon binding, the ligands rapidly activate DNA binding of acute-phase response factor (APRF), a protein antigenically related to the p91 subunit of the interferon-stimulated gene factor-3 alpha (ISGF-3 alpha). These cytokines caused tyrosine phosphorylation of APRF and ISGF-3 alpha p91. Protein kinases of the Jak family were also rapidly tyrosine phosphorylated, and both APRF and Jak1 associated with gp130. These data indicate that Jak family protein kinases may participate in IL-6 signaling and that APRF may be activated in a complex with gp130.

No abstract

The three monokines interleukin-lg (IL-IS), tumor necrosis factor a (TNFa), and interleukind (IL-6) modulate acute phase plasma protein synthesis in adult human hepatocytes. Only IL-6 stimulates the synthesis of the full spectrum of acute phase proteins as seen in inflammatory states in humans, i.e. synthesis and secretion of C-reactive protein, serum amyloid A, fibrinogen, ar-antitrypsin, q-antichymotrypsin and haptoglobin are increased while albumin, transferrin and fibronectin are decreased. IL-lb as well as TNFa, although having a moderate effect on the positive acute phase proteins and inhibiting the synthesis of fibrinogen, albumin and transferrin, fail to induce serum amyloid A and C-reactive protein.These data suggest that IL-6 plays the key role in the regulation of acute phase protein synthesis in human hepatocytes.Acute phase protein; Interleukind; Interleukin-l/I; Tumor necrosis factor a; (Human hepatocyte)

Human hepatocytes in primary culture were used as a model system to investigate the mechanism(s) involved in the induction of the acute-phase response in human liver. Hepatocytes were incubated with increasing amounts of recombinant human interleukin-1 beta, recombinant interleukin-6 and tumor necrosis factor-alpha. Synthesis of C-reactive protein was studied at the mRNA and protein levels. Only recombinant interleukin-6 was capable of inducing C-reactive protein-mRNA and C-reactive protein-protein synthesis. Also, fibrinogen and alpha-1-antitrypsin synthesis measured by immunoprecipitation with specific antisera increased in a dose-dependent, time-dependent manner, whereas albumin synthesis decreased to about 50% of controls. Maximal effects were observed at 100 to 300 units of recombinant interleukin-6/ml culture medium after 20 hr of incubation. Although the synthetic glucocorticoid dexamethasone slightly modulated the effect of recombinant interleukin-6, it was not an absolute requirement for the induction of acute-phase protein synthesis in human hepatocytes. In pulse-chase experiments it was shown that the time course of the disappearance of the acute-phase proteins from the cells and their appearance in the medium is not influenced by recombinant interleukin-6. This finding suggests that recombinant interleukin-6 exerts its regulatory effect on acute-phase protein synthesis at the pretranslational level.

Interleukin-6 (IL-6) is known to be a major mediator of the acute-phase response in liver. We show here that IL-6 triggers the rapid activation of a nuclear factor, termed acute-phase response factor (APRF), both in rat liver in vivo and in human hepatoma (HepG2) cells in vitro. APRF bound to IL-6 response elements in the 5'-flanking regions of various acute-phase protein genes (e.g., the %-macroglobulin, fibrinogen, and al-acid glycoprotein genes). These elements contain a characteristic hexanucleotide motif, CTGGGA, known to be required for the IL-6 responsiveness of these genes. Analysis of the binding specificity of APRF revealed that it is different from NF-IL6 and NF-KB, transcription factors known to be regulated by cytokines and involved in the transcriptional regulation of acute-phase protein genes. In HepG2 cells, activation of APRF was observed within minutes after stimulation with IL-6 or leukemia-inhibitory factor and did not require ongoing protein synthesis. Therefore, a preexisting inactive form of APRF is activated by a posttranslational mechanism. We present evidence that this activation occurs in the cytoplasm and that a phosphorylation is involved. These results lead to the conclusions that APRF is an immediate target of the IL-6 signalling cascade and is likely to play a central role in the transcriptional regulation of many IL-6-induced genes.During an acute inflammation, cytokines released by different cell types, including monocytes, fibroblasts, and endothelial cells, stimulate the synthesis and secretion of a set of plasma proteins, the so-called acute-phase proteins, by the liver. These proteins play a protective role during the acute-phase reaction, e.g., by inactivating proteases, supporting the wound-healing process, or scavenging free oxygen radicals (for a review, see reference 26). According to their regulation by different cytokines, acute-phase proteins have been divided into two subclasses (8). The synthesis of class 1 acute-phase proteins (e.g., a1-acid glycoprotein, C-reactive protein, haptoglobin, and serum amyloid A) is induced by interleukin-1 (IL-1) or combinations of IL-1 and IL-6, whereas the genes for class 2 acute-phase proteins (e.g., a2-macroglobulin, cxl-antichymotrypsin, and fibrinogen) are regulated mainly by IL-6 and glucocorticoids. The 5'-flanking regions of many acute-phase protein genes have been studied in detail, with the goal of identifying regulatory elements required for the cytokine induction of these genes. One type of cytokine response elements found in the promoters of several class 1 acute-phase protein genes represents binding sites for members of the C/EBP family of transcription factors (15,21,49,51,62 (36). In addition, NF-iB or NF-KB-like factors were found to be involved in the regulation of the angiotensinogen, serum amyloid A, and complement factor B genes by 48,54).Less is known about transcription factors regulating the promoters of class 2 acute-phase protein genes. On the basis of a sequence comparison of the 5'-flanking regions of the...