Interleukin mechanism

Cytokines, eg, interferons, interleukins, tumor necrosis factor (TNF), and certain growth factors, could have antitumor activity directiy, or may modulate cellular mechanisms of antitumor activity (2). Cytokines may be used to influence the proliferation and differentiation of T-ceUs, B-ceUs, macrophage—monocyte, myeloid, or other hematopoietic cells. Alternatively, the induction of interferon release may represent an important approach for synthetic—medicinal chemistry, to search for effective antiinflammatory and antifibrotic agents. Inducers of interferon release may also be useful for lepromatous leprosy and chronic granulomatous disease. The potential cytokine and cytokine-related therapeutic approaches to treatment of disease are summarized in Table 4. A combination of cytokines is a feasible modaUty for treatment of immunologically related diseases however, there are dangers inherent in such an approach, as shown by the induction of lethal disserninated intravascular coagulation in mice adrninistered TNF-a and IFN-y. 

Rot, A. (1993). Neutrophil attractant/activation protein-1 (interleukin-8) induces in vitro neutrophil migration by haptotactic mechanism. Eur. J. Immunol. 23, 303-306. 

Hormones, cytokines, interleukins, and growth factors use a variety of signaling mechanisms to facilitate cellular adaptive responses. 

Brown, G.M., Li, X.Y. and Donaldson, K. (1991a). Secretion of interleukin 1 and tumour necrosis fector by alveolar macrophages following exposure to particulate and fibrous dusts. In Mechanisms in Fibre Carcint nesis (eds. R.C. Brown, J.A. Hoskins and N.F. Johnson) pp. 499-504. Plenum, New York. 

Because of the multiple degradation pathways that may take place at elevated temperature, protein stability monitoring data may not conform to the Arrhenius relationship, and the maximum temperature selected for accelerated stability studies must be carefully selected. Gu et al. [32] described the different mechanisms of inactivation of interleukin-1 (3 (IL-1 (3) in solution above and below 39°C. In this example, the multiple mechanisms precluded the prediction of formulation shelf life from accelerated temperature data. In contrast, by working at 40° C and lower, Perlman and Nguyen [33] were able to successfully extrapolate data from stability studies of tissue plasminogen activator down to 5°C. 

Watson and Kenney [62] describe the use of high-performance size-exclusion chromatography to examine the aggregation of interferon-y and interleukin-2 after storage at elevated temperature, after mechanical agitation, and following rapid freeze-thaw. An excellent review on SEC can be found in Ref. 63. 

B31. Boermeester, M. A., van Leeuwen, P. A. M Coyle, S. M Wolbink, G. J., Hack, C. E., and Lowry, S. F., Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch. Surg. 130,739-748 (1995). 

D19. Dinarello, C. A., Okusawa, S., and Gelfland, J. A., Interleukin-1 induces a shock-like state in rabbits Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. In Molecular and Cellular Mechanisms of Septic Shock. Alan R. Liss, New York, 243-263... 

Velupillai, P. and Ham, D.A. (1994) Oligosaccharide-specific induction of interleukin-10 production by B220+ cells from schistosome-infected mice - a mechanism for regulation of CD4+ T-cell subsets. Proceedings of the National Academy of Sciences USA 91, 18—22. 

Bogdan, C., Paik, J., Vodovotz, Y. and Nathan, C. (1992) Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. Journal of Biological Chemistry 267, 23301-23308. 

Biomedical research continues to broaden our understanding of the molecular mechanisms underlining both health and disease. Research undertaken since the 1950s has pinpointed a host of proteins produced naturally in the body that have obvious therapeutic applications. Examples include the interferons and interleukins (which regulate the immune response), growth factors, such as erythropoietin (EPO which stimulates red blood cell production), and neurotrophic factors (which regulate the development and maintenance of neural tissue). 

The signal transduction mechanisms by which most interleukins prompt their biological response are understood, in outline at least. In many cases, interleukin cell surface receptor binding is associated with intracellular tyrosine phosphorylation events. In other cases, serine and threonine residues of specific intracellular substrates are also phosphorylated. For some interleukins,... 

IL-la and -ip are expressed as large (30 kDa) precursor molecules from which the mature polypeptide is released by proteolytic cleavage. Neither IL-la and -lp possess any known secretory signal peptide, and the molecular mechanism by which they exit the cell remains to be characterized. Neither interleukin appears to be glycosylated. 

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