This web page was created as an assignment for an undergraduate course at Davidson College.
My Favorite Immune Protein: Interleukin-6
Interleukin-6 (IL-6) is an immune protein in the hematopoietins family with many previous names, including interferon-ß2 (IFN-ß2), 26-kD protein, B-cell stimulatory factor-2 (BSF-2), hepatocyte stimulating factor (HSF), cytotoxic T-cell differentiation factor (CDF), interleukin-HP1 (IL-HP1), monocyte-granulocyte inducer type 2 (MGI-2), and hybridoma/plasmacytoma growth factor (HPGF/HGF), but given its final distinction as IL-6 in December of 1988. (Sehgal, et al, 1995) It is a monomer of 184 amino acids produced by T-cells, macrophages, and endothelial cells found on a single gene located at 7p21. (Ray et al., 1989) IL-6 is released in response to infection, burns, trauma, and neoplasia, and its functions range from key roles in acute-phase protein induction to B- and T- cell growth and differentiation. (Janeway, et al, 2001; Fernandez-Botran, 1995) IL-6 can have direct effects on cells, can mediate the effects of other cytokines, can be coagonistic or antagonistic in conjunction with other cytokines, and interact with glucocorticoids. (Tamm, 1989) This protein is often regarded in conjunction with the so-called interleukin-6-type cytokines: IL-11, leukemia inhibitory factor (LIF), oncostatin M (OM), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1). (Sehgal, et al, 1995)
Figure 1: Chime image of an IL-6 molecule bound to the ß chain of the IL-6 receptor. (Chow, D, et al. 2001)
IL-6 is released in response to IL-1 and TNF-b (Makinnon, 1999) The IL-6 receptor is found on many cell surfaces, including resting normal T-cells, activated normal B-cells, myeloid cell lines, hepatoma cell lines, myeloma cell lines, and on Epstein-Barr virus (EBV) modified B-cells, in which it promotes proliferation. (Hirano, et al, 1989, Tosato and Pike, 1989) IL-6 can lead to the transcription of a wide variety of proteins through all three major signal transduction pathways; protein kinase C, cAMP/protein kinase A, and the calcium release pathway. (Nakajima, et al, 1995) IL-6 has many molecular form and each molecule has a different function when secreted by different cells in distinct situations (activated through diverse stimuli). (Lee, et al, 1989; Ray, et al 1991) Its variety of functions are listed below.
IL-6 stimulates the acute-phase reaction, which enhances the innate immune system and protects against tissue damage. (Abbas, et al., 1997) It results in the release of certain proteins, called acute-phase proteins, into the blood plasma by liver cells and the decrease in rate of synthesis of other proteins. Acute phase proteins mimic antibodies but have a very broad specificity. (Janeway, et al., 2001) IL-6 increases the synthesis of the two major acute-phase proteins, c-reactive protein (CRP), which increases the rate of phagocytosis of bacteria, and serum amyloid A (SAA) by regulating changes in the gene transcription rate of these proteins. In the same way it also increases the synthesis of fibrinogen, an important clotting agent. Albumin and transferrin levels are decreased in the presence of IL-6. (Abbas et al., 1997; Kushner et al., 1990) The Acute phase local reaction leads to a systemic reaction which includes: fever, increased erythrocyte sedimentation rate, increased secretion of glucocorticoids, and the activation of the complement and clotting cascades. (Castell et al., 1989)
Figure 2: Suggested pathway of interaction leading to Secreted of IL-6 and some of its possible effects. (Fuller, 1989)
Interleukin-6 is especially important in the early stages of T-cell differentiation. In this phase, it reinforces the effect of IL-2 and promotes the differentiation of CD4 cells into T-helper2 cells. (Janeway et al., 2001; Makinnon, 1999) It controls the growth and proliferation of early progenitor cells in the thymus and bone marrow and is later important in both T-cell and Natural Killer (NK) cell activation. (Lee et al., 1989) The molecular form of IL-6 responsible for T-cell activation is released by monocytes. It augments the early events of activation, especially in CD3 T-cell receptor-mediated proliferation. (Luger et al., 1989) IL-6 also functions as the required second signal in both antigen- or mitogen-activated T-cells. (Clark, 1990) This protein holds a very important role in the life of NK cells. It is first an activator and later stimulates them to perform a more effective lysis of a pathogen. IL-6 provides support for continued development throughout the life of a natural killer cell. (Luger et al., 1989)
Interleukin-6 is very important in the stimulation of differentiation and proliferation of B-cells. (Fernandez-Botran, 1995) Its most noted effect is found in the induction of permanent differentiation of B-cells into plasma cells, antibody producing cells. (Roitt, 1991; Nawata et al., 1989) IL-6 enhances the release of antibodies by acting as a growth factor for already differentiated plasma cells. It stimulates mostly the release of IgG and IgA antibodies from these cells. (Fernandez-Botran, 1995; Abbas et al., 1997)
Although the other roles and functions of IL-6 have yet to be studied thoroughly, and more seem to appear everyday, it is known that it has major effects on haematopoiesis and thrombopoiesis and appears to be a growth factor of hybridomas and malignant cells. It appears to be especially important in such malignant cells as Kaposis sarcoma and multiple myeloma. (Fernandez-Botran, 1995; Roitt, 1991)
And if Something is Wrong?
The knockout of IL-6 has severe effects on the immune system, including a major decrease in the acute phase immune reaction and in the production of IgA antibodies. (Janeway et al., 2001) The over expression of the IL-6 gene can lead to the substantial polyclonal proliferation of plasma cells. Lack of regulation of the gene can lead to autoimmune disease and many lymphoid malignancies, including multiple myeloma. (Abbas et al., 1997; Matsuda et al., 1989) An uncontrolled or defective production of this protein most often leads to disease and is involved in the pathogenesis of many diseases and autoimmune disorders, such as liver autoimmune disease discussed below. (Tovey et al, 1989)
The knowledge of the functions of IL-6 can be very applicable in the clinical environment. First, if the acute-phase response and fever and inflammation are not controlled, they can become detrimental and lead to sepsis and shock. (Makinnon, 1999) A mutation in the gene of IL-6 has been shown to be a major player in the growth of malignant cells, most importantly multiple myeloma. (Fernandez-Botran, 1995, Matsuda et al., 1989) IL-6 is found in large amounts in, and actually produced by, the synovial tissue of patients with rheumatoid arthritis. In this setting, it induces increased production of antibodies in B-cells. (Nawata et al., 1989) Through multiple studies it has been found that patients with autoimmune liver disease, including primary biliary cirrhosis, show decreased levels of IL-6 expression, along with, not surprisingly, decreased levels of IL-1 and TNF-b . This data shows that IL-6 and the others are important in the pathogenesis of these diseases. (Tovey et al., 1989)
Drugs that Bind IL-6
Because IL-6 plays a major role in many undesired effects of the immune system, some research has been done into preventing its binding. However, it has been found somewhat more effective to bind IL-1 and TNF-b , and in this way reduce the secretion of IL-6 in the first place. One important drug in this field is the anti IL- 6 receptor antibody (MRA), used as one of new therapeutic approaches in rheumatic arthritis. (Soaud, 2002)