DNA…gene therapy…Dolly 
. We associate these words with the burgeoning field of genetics. The recent completion of the Human Genome Project has opened untold doorways into the future fabric of our lives, more so than putting a man on the moon. Already there is talk of mapping the proteome, or the proteins that our genes encode for. Specific genes have already been indicated in a number of heritable diseases such as Alzheimer's disease, Diabetes, and Sickle Cell Anemia. Recent work on the interleukin-1 beta gene has been suggested as the possible cause of stomach cancer also known as gastric cancer. How can interleukin-1 beta, a gene impossible to detect with the naked eye, be the cause of a disease as severe as cancer? Keep reading and you will soon discover why interleukin-1 beta is a big, bad, mean gene.
Ask anyone today-young children to senior citizens, if they have heard of cancer and you will probably hear yes eighty percent of the time. Cancer comes in various forms and afflicts many areas of the body. Unfortunately, a countless number of people are genetically predisposed to developing certain cancers or they live in environments, which may trigger carcinogens into action. No one is immune to cancer; it is a disease that affects both young and old. Specific types of cancer however, are predominant in certain age groups. Gastric cancer, also known as stomach cancer, is prevalent in people in their 60's and 70's (American Cancer Society 3). Statistics from the American Cancer Society web-page for gastric cancer, show that an estimated, 21,700 Americans (13,000 men and 8,300 women) will be diagnosed with stomach cancer this year alone, and that an estimated12,800 people (7,400 men and 5,400 women) will die from this disease (3). The recent completion of the human genome and advances in the medical field regarding cancer treatment leave patients with gastric cancer hopeful. Sadly, only about 10-20% of gastric cancer patients are diagnosed at an early stage, and while this gives them a better chance for survival the other 80-90% will not be diagnosed until the cancer is well established in the stomach and has possibly spread to other organs. So what happens at the genetic level to make people more prone in developing gastric cancer? Part of the answer lies in the Interleukin-1 beta (IL1B) gene and the rest lies in a bacterium known as Helicobacter pylori.
Interleukin-1: Gene Function and Structure
Interleukin-1 (IL1) is an invaluable piece of our complex immune system and has a variety of names such as the adherence promoting factor, t-cell replacing factor, Hematopoietin-1, catabolin, and IFN-beta inducing factor (Ibelgauft,1999, COPE).
In 1985, the interleukin-1gene was assigned to chromosome 2 using a cDNA probe (OMIM. Interleukin-1, Deutan series). The interleukin-1 beta gene was then localized to 2q14 by Peterson et al., who used a YAC containing the IL1RN gene as a probe in fluorescence in situ hybridization and localized the IL1RN gene to 2q14.2 (OMIM Interleukin-1, Deutan series). Researchers were then able to define the localization of the IL1-beta gene to 2q14 since the Interleukin-1 alpha gene, the Interleukin-1 beta gene, and the interleukin-1 RN gene were localized on the same chromosome at the intervals (+0 - +35kb), (+70 - 110kb), and (+330 - +430kb), respectively (OMIM Interleukin-1, Deutan series).
Interleukin-1 beta is part of the interleukin-1 family and is a pro-inflammatory cytokine and a potent endogenous inhibitor of gastric acid secretion. Interleukin-1 beta is a soluble protein that is secreted by monocytes, macrophages, and accessory cells, which are involved in the activation of T-lymphocytes and B-lymphocytes.Monocytes are one type of white blood cell that are precursors to macrophages, which are phagocytes that ingest antigens. Both monocytes and macrophages activate the T-lymphocytes (t-cells) and B-lymphocytes which are cells that defend against viral infection and intracellular protozoan parasites. Interleukin-1 is released early in an immune response by monocytes or macrophages and mediates the lymphocyte response to antigens or mitogens. Both the interleukin-1 alpha and beta forms are active, however, the beta gene is more commonly found in human immune responses while the alpha gene is found more commonly in mice (Ibelgauft,1999, COPE). Also, interleukin-1 beta is released primarily by the monocytes while interleukin-1 alpha is released by keratinocytes. Interleukin–1 beta is cleaved by an LPS-inducible protease, (LPS-lipopolysaccharide) which is immunogenic and stimulates the production of interleukin-1beta to fight endotoxins on the cellular level and viruses and parasites on the systemic level. Using electrophoretic mobility shift analysis to assess DNA binding in vitro, El-Omar et al. (2000) found that the interleukin-1 beta -31T allele was associated with a five-fold increase in DNA binding after lipopolsaccharide stimulation. Individuals carrying the interleukin-1 beta -31 T allele are more susceptible to developing hypochlorhydria and subsequently gastric cancer in the case of an infection by the bacterium Helicobacter pylori (H.pylori). Thus, the interleukin-1 beta gene is a crucial factor in determining if a person will develop gastric cancer.
Helicobacter pylori (H.pylori), is another crucial factor in determining if a person will develop gastric cancer. H. pylori was first discovered in 1983 by Australian internal medicine resident Barry Marshall and pathologist J. Robin Warren (Conrad, 2000, Cancer Control Journal)in the tissue biopsies of ulcer patients. H. pylori has 4-6 sheathed flagella which it uses to borrow through the mucous layers found in the stomach, metaplastic esophagus, duodenum, and Meckel diverticula.zThe high molecular weight of the urease enzyme lends H. pylori the ability to survive the extremes of gastric pH (Conrad, 2000, Cancer Control Journal). Urease, "catalyzes the transformation of urea to ammonium and bicarbonate, which alkalinizes the environment and protects the bacteria from gastric acid" (Conrad, 2000, Cancer Control Journal). By making the stomach environment alkaline, urease permits H. pylori to survive in an otherwise inhospitable environment and to produce proteases, lipases, phospholipases, and cytotoxins, thereby contributing to the pathogenicity of the bacterium.
Gastric CancerThe research of El-Omaret al., implicates that host genetic factors which affect the interleukin-1 beta gene may determine why some individuals infected with H. pylori develop gastric cancer and why others do not (OMIM, Interleukin-1, Deutan Series). Gene cluster polymorphisms in the interleukin-1 beta gene are responsible for certain Individuals that develop gastric cancer show lower levels of gastric acid in their stomachs while those that do not develop gastric cancer or that develop ulcers have higher levels of gastric acid. Lower stomach acid may be a future indication of gastric cancer susceptibility and that interleukin-1 gene cluster polymorphisms may be responsible for a malfunctioning interleukin-1 beta gene that lowers levels of gastric acid in the stomach making individuals with this mutation more vulnerable to gastric cancer. The " three diallelic polymorphisms in IL1B [which] have been reported, all [represent] C-to-T base transitions, at positions –511, -31, and +3954 basepairs from the transcriptional start site" (OMIM, Interleukin-1, Deutan Series). El-Omar et al., demonstrated that individuals who were "carriers for the interleukin-1 beta- 31T allele had low acid secretion and that there was little difference between homozygous and heterozygous carriers" since the "pro-inflammatory genotypes of the IL1 loci (IL1B- 31T and IL1RN/ IL1RN*2) increase both the likelihood of a chronic hypochlorhydric response to H. pylori infection and the subsequent risk of gastric cancer, presumably by altering IL1-beta levels in the stomach" (OMIM, Interleukin-1, Deutan series). The C-to-T transition at the -31 site involves the TATA sequence in the IL1B promoter and using "eletrophoretic mobility shift analysis to assess DNA binding in vitro" researchers found that the "IL1B -31T allele was associated with a 5-fold increase in DNA binding after lipopolysaccharide stimulation" subsequently making people with the IL1B mutation likelier candidates for hypochlorhydria and gastric cancer after H. pylori infection.
The complexity of the signaling process demonstrates the intricacy of our genes and how the interleukins work in our body in our immune responses. Technological advancements in screening techniques and the recent completion of the human genome advance our fight against cancer by providing the hope for gene therapy so we can avoid the possibility of developing cancers that may be preventable through screening and gene treatment. By continuing to map other organisms we will learn more about ourselves as humans and why some individuals are marked for certain diseases.
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