IL-6 and cancer

Interleukin-6 (IL-6) is a pleiotropic cytokine that is involved in the physiology of virtually every organ system. It is secreted by T-cells and macrophages to stimulate immune response. Its deregulation also impacts many types of cancer. IL-6 gene transcription is induced in many different normal tissues in response to stimuli, such as virus infection, bacterial endotoxin, LPS, and serum. Efficient induction of IL-6 promoter requires C/EBP family members, NF-kB and NF-IL6. Its promoter is also inhibited by p53 and Rb. There are two different IL-6 receptors which can associate directly with IL-6. One is membrane bound form the other is soluble form. Soluble IL-6 receptor (sIL-6R) can bind IL-6 and induce homodimers or heterodimers of glycoprotein 130 which is also called IL-6R betta chain. The three components of this complex can induce signal transduction by activation of cytoplasmic tyrosine kinase (JAK pathway) and modification of transcription factors (phosphorylation of STAT1 and STAT3). It has been found that an elevated serum IL-6 level correlated with and adverse prognosis in patients with several different typrs of cancer, including multiple myeloma, lymphoma, ovarian cancer, prostate cancer, and metastatic renal cell carcinoma. IL-6 in the serum or plasma from patients may be present in several different forms, including high-moleculer-weight complexes that contain sIL-6R, anti-IL-6R antibodies, or small chaperone proteins. To date, a role for IL-6 has been implicated in almost every cancer examined. In breast cancer, IL-6 inhibits the growth of breast cancer cells either alone or in combination with THF-α and IL-1. IL-6 also may be involved in inducing migration and metastases, and confer muti-drug resistance in breast cancer cells. In colon cancer, IL-6 exhibited growth-stimulatory effects on a panel of colon cancer cell lines. Recent studies also suggested that inflammation and IL-6/IL-6R expression play a role in the pathogenesis of colon cancer. In lung cancer, IL-6 may have an inhibitory effect on the growth of lung cancer although some studies suggest a correlation between IL-6 level and disease status. In multiple myeloma which is one of the most studied tumor types in relation to IL-6, preclinical, translational correlations and early Phase I studies suggest that blocking IL-6 production may lead to effective therapy. There are still many different cancers related with IL-6. Indeed, IL-6 is one of the most ubiquitously deregulated cytokines in cancer, and increased levels of IL-6 have been observed in virtually every tumor studied. Therapeutic targeting of IL-6 and its receptor in cancer has strong biologic rationale, and there is preliminary evidence suggesting that targeting of the IL-6 system may be beneficial in the treatment of cancer.
More information about this paper can be found from http://www3.interscience.wiley.com/cgi-bin/fulltext/116316741/HTMLSTART

TNF antagonist therapy

In the article "New Therapeutic Approaches for Spondyloarthritis" we are told the relative effectiveness of three TNF-a antagonist therapies, including infliximab, etanercept, and adalimumab. In the beginning sections of the article we are told that inhibiting TNF will reduce spine inflammation in active AS (ankylosing spondyloarthritis) and inhibit the structural disease progression due to inflammation. In the conclusion paragraphs, we also are reminded that the inhibition of TNF is a successful therapy for decreasing and eliminating spinal inflammation. However, in the middle paragraphs describing the studies using infliximab, etanercept, and adalimumab, the actual "inhibition of TNF" is never mentioned or described. They were introduced as "TNF-a antagonist therapies," but in their descriptions and discussions the mechanism for this inhibition is never touched on. I would be interested to read more about how the TNF is inhibited, such as where in the spine their activity is halted, how fast the therapies occur, how they are performed, etc. Also, throughout the article, it is supported that the inhibition of TNF will decrease deterioration and inflammation, but the author also continues to mention that these therapies did produce compelling argumments regarding structural disease modification. I find this interesting to mention, since all the experiments are studying is the inhibition of TNF, and this would have no affect on structural modification besides the reduction of inflammation. If structural modification, such as the inhibition of the inflammation and degradation in addition to rebuilding lost tissues and bone, was the intent, an additional enzyme or catalyst must be used that will promote the rebuilding. For example, just as TNF was inhibited in the sacrum and iliac crest in these therapies, osteoblast production should be promoted by an activator to in turn promote rebuilding the bone lost to AS. This is a good start to curing and preventing AS, however it is only a start. Now that we have the beginnings of the therapies to stop the disorder, we should begin looking for the second half of therapy which is repair/rebuilding and prevention for future attack.

New therapeutic approaches for spondyloarthritis

Ankylosing spondylitis is a chronic, inflammatory disease that has structure-modifying effects from tumor necrosis factor alpha inhibition. Tumor necrosis factor antagonist therapy may suggest some benefit, at least in the short term.
Before this treatment, ankylosing spondylitis therapy included suppression of inflammatory response usually with nonsteroidal anti-inflammatory drugs to delay disease progression. However, new treatment are based on tumor necrosis factor antagonists suchs as humira, enbrel, and remicade that have all been approved by the US Food and Drug administration for the treatment of ankylosing spondylitis. All of these drugs had studies performed on them, and the results were given in the articles.
Studies were performed for these three treatments, but concerns with the study include the lacking of true placebo groups because NSAID therapy alone may reduce radiographic progression in ankylosing spondylitis. Also, there is no reliable method to predict at an early stage wich ankylosing spondylits patients will develop significant structural damage.
The reason I LOVED this article was because at the end of every study, the authors gave reasons why the study may not be valid. When reading these reports, it is often difficult to understand what is being studied and what the results imply. Even if you do understand this part, it is still difficult to understand if the study was valid or not. This paper gives examples of how to critique and analyze studies.

Reactive Oxygen species and Their Role in Joint Diseases

Superoxide anion O2- is a member of the reactive oxgen species (ROS) and is a significant factor in inflammation, particularly in patients with inflamamatory joint disease. This radical is neutralized by the enzyme superoxide dismutase (SOD) that converts O2- into hydrogen peroxide (H2O2). However, if not transformed by this enzyme, the superoxide anion can react with NO to cause cartilage damage. SOD protects against the harmful effects of superoxide anion, and several SOD mimetics have been developed for reducing inflammation.
The concentrations of ROS are governed by the balance between the production of ROS and their elimination antioxidants such as vitamin E, Carotenoids, and bilirubin. SOD1 plays a key role in cell survival and growth, but overproduction of TNF-a inhibits the SOD1 antioxidant enzyme expression. SOD2 provides protection against ROS generated by hypoxia, and deficiency of SOD2 increases O2- in mitochondria. SOD3 protects cells agains O2- generated by neutrophils.
SOD mimetics decrease the inflammatory process by decreasing peroxynitrite formation leading to greater bioavailability of NO, decreased neutrophil sites of inflammation, and decreased release of proinflammatory cytokines. However, after reading all of the articles, it does seem as though TNF-a is by far the most important factor in alleviating inflammation of these diseases

The Role of Macrophages in rheumatoid arthritis

Rheumatoid arthritis is generally considered to be a chronic inflammatory autoimmune disorder that causes the body's immune system to attack its own joints. RA can result in loss of mobility due to pain and joint destruction. Although the cause of RA is unknown, macrophages and their products appear to play a key role in RA pathology. Monocytes in peripheral blood differentiate into synovial-tissue macrophages which produce numerous inflammatory mediators such as cytokines, growth factors, chemokines and proteases. Macrophages also express adhesion molecules, chemokine receptors and surface antigens that allow the macrophages to interact with other cells and ECM molecules. It is also important to recognize that macrophages may differentiate into osteoclasts, which further to joint destruction.
Factors such as Mcl-1 (an antiapoptotic factor) found on the surface of macrophages appear to have increased expression in RA macrophages. Increased expression of Mcl-1 would cause a resistance to apoptosis in synovial tissuse, which plays a role in the persistence of RA since the affected tissue is unable to self-destruct and make way for new, healthy tissue.
Products secreted by synovial tissue macrophages also contribute to RA. Interleukin-1 (IL-1) and TNF-a are the main proinflammatory cytokines secreted. TNF-a also stimulates the production of IL-6, IL-8/CXCL8, ENA-78/CXCL5, MCP-1/CCL2 and MIP-1a/CCL3, which are all secreted by macrophages.
IL-10, another synoival tissue macrophage secretory product, is normally thought of as an anti0inflammatory cytokine, however, this is not true for RA. It has recently been found that IL-10 induces TNF-a receptor expression on monocytes. Also, when IL-10 was stimulated, the expression of interferon-gamma-inducible genes was increased . Interferon-gamma-inducible proteins have been shown to have proinflammatory but antiangiogenic effects in RA.
Macrophage migration-inhibatory factor (MIF) is another cytokine produced by synovial tissue macrophage. MIF is shown to stimulate TNF-a, IL-1, IL-6, IL-8 and MMP production. MIF exresssion in RA is stimulated by glucocorticoids, which means that the antiinflammatory effects of glucocorticoids are overridden by MIF. MIF seems to be the most interesting and promising recently researched cytokine due to the many effects produced by the molecule.
There are numerous other factors expressed on the surface of or secreted by synovial tissue macrophages in addition to the examples described above. Therefore targeting macrophages and their products may be the key to treating RA.

Macrophage polarization: more than just an “on/off” switch

To quote Alberto Mantovani: “Heterogenicity and plasticity are the hallmarks of cells belonging to the monocyte-macrophage lineage” (2,3). Monocytes leave the bone marrow, circulate to nearly every tissue, and then differentiate into macrophages: a process which is poorly understood (1,2,3). While our focus will be the variety of macrophage functional states, monocytes have functionality too! In fact, a subclass of IL-4aR+ monocytes are called “myeloid suppressor cells”, secrete IL-4 and IL-13, and can suppress the function of CD8+ cytotoxic T cells (2). Some human monocytes have even been observed to proliferate (8).
Once the monocyte enters into tissue, it becomes a macrophage with a functional activation state specific to the tissue as well as the local microenvironment (inflammation, infection, damage, age, etc.) (4,6). While the properties of tissue macrophages do “drift” with age, this has been shown to be caused by the tissue milieu and not due to any age-associated defect in the macrophages (4), and is reversible (6). Instead of an “on-off” switch, macrophage activation is a continuum: controlled not only by what cytokines are introduced (4), but also when (4,6). Macrophage function can also be continuously modified throughout the life of a cell, with IFN-γ stimulation exhibiting the most dramatic “resetting” (6). A “giant cell” is an extreme example of macrophage function, and also an exception to the general concept of macrophage plasticity (2,3). Giant cells are similar in appearance to osteoclasts (bone marrow macrophages) (6) in that they appear to be single cells with many (2-10+) nuclei, but are associated with granulomas formed by bacteria like M. tuberculosis (2,3). Although the specific function of these polynucleated macrophages is unknown, the formation process appears to be driven by CD44 and the nucleotide receptor P2X7, which is largely IL-4 associated (and thus M2: see below) (2,3).
The most common activation states of macrophages are “M1” and “M2”, mirroring the Th1 and Th2 nomenclature (3). M1 is referred to as “classical” activation, typically in response to bacterial infection or tissue damage, and can be induced by IFN-γ, LPS, TNF-α or GM-CSF (granulocyte/monocyte colony stimulating factor) (2,4). M1 macrophages are also referred to as “angry” due to their vastly increased iNOS levels, IL-1β, IL-6 and TNF-α production; they are both inducers and effectors of a Th1 response (2,3,6). Physiologically, M1 cells are effective against bacteria and intracellular parasites as well as tumors (2,3,8). M2 is unfortunately referred to as the “alternative” activation, i.e. every macrophage not expressing classical M1 functionality. M2 activation is typically induced by IL-4, IL-13, and IL-10 as well as glucocorticoids (2,4). M2 macrophages are largely considered to be pro-growth and anti-inflammatory, as they have increased arginase activity (in mouse, though not human, ref 8), increased scavenger receptor expression, increased secretion of IL-10 and TGF-β, and decreased expression of IL-1β (2,3,6). M2 cells promote the killing and encapsulation of parasites, tissue repair and remodeling, stimulation of a Th2 response (2,6,8), scarring (3), immunoregulation of T cell function (5), and are more recently associated with increasing tumor growth and progression (2,9). Phagocytosis can be performed by both M1 and M2 macrophages, and its complex regulation is beyond this brief summary. More specialized (and rare) macrophage phenotypes exist, such as either “M3” or “M4”, all depending upon different external stimuli (4).
In terms of human disease, high levels of IL-6 (M1 product) act to perpetuate chronic inflammation in the liver, leading to cancer (1). Interestingly, estrogens (acting through NF-κB) attenuate liver macrophage IL-6 production and induce an M2 phenotype, possibly explaining some of the gender discrepancy in liver cancer incidence (1). Similiarly, IL-1 can convert a steroid androgen receptor modulator (SARM) into a tumor-promoting transcription agonist (1). Inflammation resulting from head trauma can cause microglia (brain macrophages) to become M1, highly motile and neurotoxic (6). While it appears that M1 macrophages are associated with tissue damage and produce an environment favorable for tumor promotion, macrophages from tumor-bearing animals show an M2 phenotype (6,7,9), indicating that macrophages can be pathogenic regardless of activation state.
The story continues to evolve, with more work focusing on human macrophages as transcript analysis identifies significant expression differences between mouse and man (8). It is clear, however, that macrophage function is finely tuned by local stimuli, and is therefore entirely context dependent.

(1) Mantovani, A. Nature. 2007: 448(7153), pp 547-8
(2) Mantovani, A., et. al. Eur. J. Immunol. 2007: 37(1), pp14-16
(3) Mantovani, A., et. al. Immunity. 2005: 23(4), pp 344-6
(4) Stout, R.D. and Suttles, J., Immunol. Rev. 2005: 205, pp 60-71
(5) Nair, M.G., et. al. J. Immunol. 2006: 177(3), pp 1393-9
(6) Stout, R.D., et. al. J. Immunol. 2005: 175(1), pp 342-9
(7) Luo, Y., et. al. J. Clin. Invest. 2006: 116(8), pp 2132-41
(8) Martinez, F.O., et. al. J. Immunol. 2006: 177(10), pp 7303-11
(9) Redente, E.F., et al. Am. J. Pathol. 2007: 170(2), pp 693-708