Il 6 hämmare
Synergistic immunotherapy of glioblastoma by dual targeting
Metrics details. IL-6 is a pleiotropic cytokine with a wide range of biological activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Its activities are shared by ILrelated cytokines such as leukemia inhibitory factor and oncostatin M. The pleiotropy and redundancy of IL-6 functions have been identified il 6 hämmare using a unique receptor system comprising two functional proteins: an IL-6 receptor IL-6R and gp, the common signal transducer of cytokines related to IL Signal transduction through gp is mediated by two pathways: the JAK—STAT Janus family tyrosine kinase—signal transducer and activator of transcription pathway and the Ras mitogen-activated protein kinase pathway.
The negative regulators of IL-6 signaling have also been identified, although the physiological roles of the molecules are not yet fully understood. The pathological roles of IL-6 have also been clarified in various disease conditions, such as inflammatory, autoimmune, and malignant diseases.
On the basis of the findings, a new therapeutic approach to block the IL-6 signal using humanized anti-IL-6R antibody for rheumatoid arthritis, Castleman's disease, and multiple myeloma has been attempted. IL-6 was originally identified as an antigen-nonspecific B-cell differentiation factor in the culture supernatants of mitogen- or antigen-stimulated peripheral blood mononuclear cells that induced B cells to produce immunoglobulins [ 12 ], and was named B-cell stimulatory factor 2 BSF Simultaneously, IFN-β2 [ 45 ] and a kDa protein [ 6 ] in fibroblasts were independently cloned by different groups and found to be identical to BSF Although various names have been used for this molecule because of its multiple biological activities, it is now known as IL A pleiotropic cytokine with a wide range of biological activities Fig.
It induces growth of T cells and differentiation of cytotoxic T cells [ 15 — 19 ] by augmenting the expression of IL-2 receptor il 6 hämmare 15 ] and the production of IL-2 [ 20 ].
Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms
IL-6 acts synergistically with IL-3 to support the formation of multilineage blast cell colonies in hematopoiesis [ 21 — 25 ]. IL-6 also induces differentiation of macrophages [ 26 ], megakaryocytes [ 27 — 29 ], and osteoclasts [ 30 ]. In the acute-phase reaction, this cytokine stimulates hepatocytes to produce acute-phase proteins such as C-reactive protein CRPfibrinogen, α 1 -antitrypsin, and serum amyloid A [ 1213 ], and it simultaneously suppresses albumin production [ 11 ].
It causes leukocytosis and fever when administered in vivo [ 31 ] and also acts as a growth factor for renal mesangial cells [ 32 ], epidermal keratinocytes [ 3334 ], and various types of tumor cells, for example, in plasmacytoma [ 8 ], multiple myeloma [ 35 ], and renal cell carcinoma [ 36 ]. ILproducing cells and biological activities of IL IL-6 is produced by lymphoid and nonlymphoid cells, such as T cells, B cells, monocytes, fibroblasts, keratinocytes, endothelial cells, mesangial cells, and several kinds of tumor cell top of figure.
IL-6 also has a wide range of biological activities on various target cells bottom of figure. Although IL-6 has pleiotropic effects on various target cells, some of the biological activities are also mediated by other cytokines, such as leukemia inhibitory factor LIF and oncostatin Il 6 hämmare OSM. The pleiotropy and redundancy of IL-6 functions can be identified by using a unique receptor system of cytokines [ 14 ].
We and our colleagues identified the two components of IL-6 receptor IL-6Ran kDa ILbinding protein α chain and a kDa signal transducer known as gp β il 6 hämmarein and [ 37 — 39 ], respectively. Another feature of cytokines is the redundancy of their functions. For example, IL-6, LIF, and OSM all induce macrophage differentiation in the myeloid leukemia cell line M1 [ 40 — 43 ] and acute-phase protein synthesis in hepatocytes [ 111244 — 46 ].
An important finding as regards cytokine receptors is that one constituent of a given cytokine receptor is shared by several other cytokine receptors [ 47 ].
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Thus, the molecular mechanisms of redundancy in functions of cytokines of the IL-6 superfamily can be explained at least in part by the sharing of gp among their receptors. A complex consisting of a soluble cytokine receptor and its corresponding cytokine acquires different target specificity from the original cytokine and should therefore express different functions from those of the original cytokine.
In fact, we found that doubly transgenic mice expressing human IL-6 and IL-6R showed myocardial hypertrophy [ 50 ], indicating that the combination of IL-6 and soluble IL-6R acts on heart muscle cells that express gp, an action that IL-6 cannot exert by itself. The action leads to the induction of cardiac hypertrophy, so that the effect is similar to that of cardiotrophin This combination of cytokine and its soluble receptor may contribute to the generation of the functional diversity of cytokines in a wide range of other receptor il 6 hämmare and may also play a pathological role in various diseases in which an increase il 6 hämmare the serum-soluble form of various cytokine receptors has been reported.
As the cytoplasmic domain of most cytokine receptors, including gp, does not have an intrinsic catalytic domain, one of the most controversial issues before was the identification of catalytic molecules that associate with cytokine receptors. Furthermore, the signal transducer and activator of transcription STAT was found to play a central role in a variety of cytokine signal cascades.
This finding suggests that there is a hierarchy among gpassociated JAKs [ 55 ].
The paradigm of IL-6: from basic science to medicine
Several research groups, including ours, have identified two types of IL-6 response element IL-6RE in the genes encoding acute-phase proteins. IL-6 triggers the rapid activation of a nuclear il 6 hämmare, known as the acute-phase response factor, which binds to type II IL-6RE [ 60 ]. Purification and molecular cloning of this factor revealed that it is identical to STAT3 [ 5461 ].
We clarified that human gp has amino acid residues in its cytoplasmic domain, which contains two motifs, Box1 and Box2, conserved among the cytokine receptor family Fig. The membrane-proximal region containing Box1 and Box2 was found to be sufficient for the activation of JAK through gp [ 64 ]. Furthermore, human gp has six tyrosine residues in its cytoplasmic domain.
Finally, the tyrosine phosphorylation of Src homology protein 2 tyrosine phosphatase-2 SHP-2a phosphotyrosine phosphatase, and that of STAT3 depend on the second tyrosine residue Y2 from the membrane, and on any one of the four tyrosine residues Y3, Y4, Y5, Y6 in il 6 hämmare carboxy terminus that have a glutamine residue at the third position behind tyrosine Y-X-X-Q see Fig.
Schematic structure of gp This is followed by the tyrosine phosphorylation of the distal part of gp and recruitment of STAT3. It is known that IL-6 induces growth arrest and macrophage differentiation in the murine myeloid leukemic cell line M1.