Cytokine synthesis

Cytokines. Figure 1 Inhibition of cytokine synthesis during activation of the specific immune system. The monoclonal antibodies Muromonab and Basiliximab are specific for the CD3 complex of the T-cell receptor, and for the IL-2 receptor on lymphocytes, respectively. Cyclosporin and Tacrolimus inhibit activation of cytoplasmic NF-AT, a transcription factor essential for activation of the IL-2 gene ( NFAT Family of Transcription Factors). Sirolimus interferes with mTOR signaling and inhibits IL-2 dependent proliferation. Red pharmaka, blue target proteins. 

In addition to inhibiting cytokine synthesis by glucocorticoids, cytokine effects can be prevented by scavenging the cytokine either with neutralizing antibodies or soluble receptors or by blocking the respective cytokine plasma membrane receptors with blocking antibodies or receptor antagonists. 

Cyclosporine A (CsA) is a water-insoluble cyclic peptide from a fungus composed of 11 amino acids. CsA binds to its cytosolic receptor cyclophilin. The CsA/cyclophilin complex reduces the activity of the protein phosphatase calcineurin. Inhibition of this enzyme activity interrupts antigen receptor-induced activation and translocation of the transcription factor NEAT to the nucleus which is essential for the induction of cytokine synthesis in T-lymphocytes. 

Tacrolimus (TRL), in the past also named FK506, belongs to the group of macrolides and is produced by a special actinomycete species. TRL binds to its cytosolic receptor FKBP-12, however, it also blocks calcineurin activity and subsequently cytokine synthesis. 

Colantonio L, Rossi B, Constantin G, D Ambrosio D. Integration and independent acquisition of specialized skin- versus gut-homing and Thl versus Th2 cytokine synthesis phenotypes in human CD4+ T cells. Eur J Immunol 2004 34 2419-2429. 

The results obtained from the academic stress and older AD caregivers suggest that the tendency of a stress-induced shift in Thl toward Th2 pattern of cytokine synthesis is not absolute, and that humoral immunity is also subject to suppression by stress. We conclude this based on results showing stress-induced changes in both the antibody and T-cell response components of the immune response.54 57... 

Faith A. Akdis CA. Akdis M, Joss A, Wymann D. Blaser K An altered peptide ligand specifically inhibits Th2 cytokine synthesis by abrogating TCR signaling. J Immunol 1999 162 1836-1842. 

Kitamura M, Suto T, Yokoo T, Shimizu F, Fine LG Transforming growth factor-(Jj is the predominant paracrine inhibitor of macrophage cytokine synthesis produced by glomerular mesangial cells. J Immunol 1996 156 2964-2971. 

Pan et al., 2005). Regardless of the specific mechanism involved, the dn-CaMKIV and Camk4 1 mouse models together with the human naive T cell results clearly show that CaMKIV is required to activate T cell cytokine synthesis in response to TCR stimulation. The point at which CaMKIV acts in the different types of T cells is summarized in Figure 4. 

E. A. Abordo and P. J. Thomalley, Pro-inflammatory cytokine synthesis by human monocytes induced by proteins minimally modified by methylglyoxal, in F, 1998, 357-362. 

Vieira, P., de Waal-Malefyt, R., Dang, M. N., Johnson, K. E., Kastelein, R., Fiorentino, D. F., de Vries, J. E., Roncarolo, M. G., Mosmann, T. R., and Moore, K. W. (1991). Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones Homology to Epstein-Barr virus open reading frame BCRFl. Proc. Natl. Acad. Sci. USA 88, 1172-1176. 

Enhances MHC class II expression, tumoricidal activity and cytokine synthesis by monocytes... 

In summary, it is clear that cytokines play a critical role in the regulation of both the amount and the class of immunoglobulins secreted by B lymphocytes at mucosal surfoces. Conversely, B lymphocytes themselves may influence local cytokine synthesis by T lymphocytes, as exemplified by their differential capacity to present soluble antigens to ThI and Th2 T lymphocytes (described previously). 

De Waal-Malefyt, R., Abrams, J., Bennett, B., Figdor, C.G. and De Vries, J.E. (1991a). Interleukin-10 (IL-10) inhibits cytokine synthesis by human monocytes an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 174, 1209-1220. 

The studies of mast cell cytokine production described above have shown that maximal induction of cytokine synthesis and release usually occurs in response to IgE-dependent activation. In common with many cell types, there is evidence that FccRI on mast cells is coupled to the phospholipase C effector system that controls two distinct signal transduction pathways, one regulated by Ca " ions and the other by protein kinase C (PKC). Exocytotic degranulation is associated with an increased cytoplasmic level of Ca ions, and activation of mast cells can be therefore achieved by the use of calcium iono-phores which raise intracellular calcium concentrations through a receptor-independent mechanism. Alternative mast cell stimuli include phorbol-12-myristate-13-acetate (PMA) which activates PKC and induces mediator secretion from basophils and rodent mast cells but not from human mast cells, and concanavalin A (Con A), a lectin which can stimulate mast cells by cross-linking of cell-bound IgE and/or cell surface glycoproteins. 

IL-10, previously known as cytokine synthesis inhibitor factor (CSIF), was originally identified as a product of murine Th2 clones that suppressed the production of cytokines by ThI clones responding to stimulation of antigen (Fiorentino etal., 1989). In humans, ThO, ThI and TH2-like T cell clones, activated monocytes... 

IL-13 is a recently described cytokine secreted by different human T cell subsets and is a potent modulator of human monocyte and B cell function (Minty et al., 1993). Both CDT" and CDB" T cell clones synthesize IL-13 in response to antigen-specific or polyclonal stimuli (Zurawski and De Vries, 1994). IL-13 has profound effects on human monocyte morphology, surface antigen expression, antibody-dependent cellular toxicity and cytokine synthesis (Minty et al., 1993 McKenzie et al., 1993). In human monocytes stimulated by LPS, the production of proinflammatory cytokines, chemokines... 

Other drugs may also have an inhibitory effect on cytokine synthesis. Elevation of cyclic AMP has an inhibitory effect on ID2 release from lymphocytes in vitro (Didier et al., 1987) and this may be achieved by theophylline at high plasma concentrations. Selective phosphodiesterase inhibitors may also be effective and recently phosphodiesterase IV inhibitors have been demonstrated to inhibit the release of IL-4 and IL-5 from T lymphocytes in vitro (Essayan et al., 1993). 

---