Lymphokines and Related Peptides、淋巴激酶及相關(guān)肽的介紹

Definition

Lymphokines (lymphocyte-derived cytokines) are soluble proteins that act as local hormones that are produced by a type of immune cell known as a lymphocyte. They possess powerful immunoregulatory properties.

Discovery

Dumonde et al., in 1969 first described lymphokines as non-antibody mediators of cellular immunity generated by lymphocyte activation. They showed that four principal features of cellular immunity in the guinea-pig are mediated by a group of soluble factors generated by antigen-activated lymphocytes and these "lymphokines" are different from classical antibodies. They suggested that lymphokine factors are involved both in the peripheral expression of cell-mediated immunity and in regulation of the immunological response; that their significance may be fundamental to mechanisms of cellular surveillance; and that in evolution, their origin may have run parallel with the development of adaptive immunity 1, 2.

Structural Characteristics

Molecular cloning of lymphokine cDNAs has revealed that each lymphokine is composed of a single polypeptide containing a hydrophobic signal sequence at the NH2 terminus characteristic of secretable proteins. Sequences of lymphokines are well conserved between mouse and human and, generally, homology at the nucleotide level is about 70% and that at the amino acid level is 50%. However, mouse and human IL 3’s share only limited homology (29%) at the amino acid level. Most lymphokines show no obvious homology with other growth factors or oncogenes and no significant homology are found between lymphokines at either the nucleotide sequence or amino acid sequence level 3.

Mode of Action

The inactivation and clearing of infectious agents through adaptive immune responses results from interactions between T lymphocytes, B lymphocytes and mononuclear phagocytes. The effector cells in cell-mediated immunity (CMI) are primarily T lymphocytes and mononuclear phagocytes. CMI responses appear in two stages, lymphocyte activation with subsequent production of biologically active mediators, and recruitment and activation of other cells (particularly mono-nuclear phagocytes) as a result of the activity of several of these mediators. Collaboration between T lymphocytes and macro-phages in bacterial infections mediated by a lymphokine that causes inhibition of the growth of organisms within the macro-phage has been assayed. This inhibition probably results from increased macrophage microbiocidal activity. Lymphokine reduces the viability of bacteria. The mechanism of action of this lymphokine is impairment of the ability to divide of otherwise metabolically active bacteria 4.

Functions

In auto immunity: Lymphokines, in particular interferons (IFN), tumor necrosis factor (TNF), and interleukins 1 and 2 (IL-1, IL-2) often synergize and interact, and can mediate several prominent clinical and laboratory manifestations of autoimmunity. Patients undergoing therapy with IFN or IL-2 may develop varied autoimmune syndromes, often an exacerbation of previously latent autoimmunity. The administration of IFN to experimental animals can cause or accelerate autoimmune disease and, more importantly, specific lymphokine blockade was shown to be protective. Finally, aberrant MHC class II expression on nonlymphoid cells can be identified in the target organs of most autoimmune diseases and extensive data suggest that it can present autoantigen, activate autoreactive T cells, and initiate a cascade of self-propagating autoimmunity. In conclusion, several lymphokines, produced mainly locally and interacting with each other, have an important role in the pathogenesis of autoimmunity 5.

Different cellular functions: Lymphokines encourage cell growth, promote cell activation, direct cellular traffic, destroy target cells, and incite macrophages. A single cytokine may have many functions; conversely, several different cytokines may be able to produce the same effect 6.

Antiviral action: One of the first cytokines to be discovered was interferon. Produced by T cells and macrophages (as well as by cells outside the immune system), interferons are a family of proteins with antiviral properties. Interferon from immune cells, known as immune interferon or gamma interferon, activates macrophages, which clear virus infected cells 6.

Killing of tumor cells: Two other cytokines, closely related to one another, are lymphotoxin (from lymphocytes) and tumor necrosis factor (from macrophages). Both kill tumor cells; tumor necrosis factor (TNF) also inhibits parasites and viruses 6.

Activation of lymphocytes: Different lymphokines promote the activation, growth and differentiation of T and B lymphocytes, macrophages, and hemopoietic cells. Lymphokine production is associated with, but not limited to, helper T cells, and usually follows antigenic or mitogenic stimulation. The recognition that some lymphokines are produced after stimulation of neoplastic T cells has proved advantageous in the study of these molecules. T cell tumors are monoclonal, grow easily in vitro, and may produce fewer lymphokines than normal T cells. Thus, the purification and biochemical and biological characterization of some lymphokines have been facilitated by the availability of these tumors. More recently, T cell tumors have been used for evaluating the molecular structure of lymphokine-encoding genes. They have also provided information relevant to our understanding of the nature of T cell neoplasia 7.

References

1. Dumonde DC, Wolstencroft RA, Panayi GS, Matthew M, Morley J, Howson WT (1969). Lymphokines: Non-Antibody Mediators of Cellular Immunity generated by Lymphocyte Activation. Nature, 224:38-42.

2. Dumonde DC (1970). Lymphokines: Molecular Mediators of Cellular Immune Responses in Animals and Man. Proc. roy. Soc. Med., 63:899-902.

3. Miyajima A, Miyatake S, Schreurs J, De Vries J, Arai N, Yokota T, Arai K (1988). Coordinate regulation of immune and inflammatory responses by T cell-derived lymphokines. Faseb J., 2:2462-2473.

4. Bloom BR (1971).  In vitro approaches to the mechanism of cell-mediated immune reactions. Adv. Immun., 13:101–208.

5. Schattner A (1994). Lymphokines in autoimmunity--a critical review. Clin Immunol Immunopathol., 70(3):177-189.

6. Feldmann M, Londei M, Haworth C (1989). T cells and lymphokines. British Medical Bulletin, 45:361-370.

7. Corley RB, Dexter CM, Ovnic M (1986). Inducible lymphokines of T cell tumors. Crit Rev Immunol., 6(1):71-103.