Inflammation's infamy

Courtesy of Keith Crutcher IMMUNITY IN MIND: Cultured microglial (N9) cells (red) on a tissue section containing an Alzheimer plaque (green). There is continuing controversy about whether these types of inflammatory cells are responding to plaques or causing them. A finger catches the sharp edge of an envelope; a noseful of tree pollen is accidentally inhaled; the latest virus finds host after human host. In all cases the assaulted body reacts through inflammation, a well known, but not well defined process, especially its molecular cascade of events. These events are orchestrated by chemokines and the other biochemicals of innate immunity, eventually engaging downstream immune cells and antigens involved with adaptive immunity. A person is born with an innate immune system, whereas acquired immunity is developed through lifelong contact with pathogens. Usually, inflamed tissue heals quickly, end of story. But when things go awry, the downstream immunological events, both innate and acquired, can lead to several disparate diseases. "I personally believe that chronic inflammation is the root of all evil," says Emad El-Omar, professor of gastroenterology, University of Aberdeen, UK, who works on host genetic factors associated with gastritis, a condition tied to Helicobacter pylori-related inflammation. Over the past 10 years, inflammation has been implicated as both cause and aggravating effect in a growing number of widespread, often unrelated ailments, including atherosclerosis, Alzheimer disease (AD), and some cancers. The cancer connection: Some evidence suggests a link between inflammation and angiogenesis. Other studies link cancer to the enzyme cyclooxygenase-2 (COX-2), which is involved in inflammation. In Alzheimer disease, an important risk factor, apolipoprotein E4 (apoE4) is expressed in cells that are part of an inflammatory response to nervous system injury. In such complex diseases, it's difficult to point to inflammation as cause or symptom, but the link remains. As examples mount, Keith Crutcher, professor of neurosurgery at the University of Cincinnati, notes, "It doesn't take a brain scientist to say maybe there's something going on here." In many cases, infection plays a role, but the real problem starts with the development of chronic inflammation. Just how chronic inflammation becomes unremitting is still unknown. Even the definition of inflammation is a problem, says pathology professor Robert M. Strieter, David Geffen School of Medicine, University of California, Los Angeles. Different pathways connect the initial inflammatory response with adaptive immunity, making it impossible to formulate a single definition. "Many people look at inflammation and think it's all the same, but in many ways it's not .... It is how it begins to go from a nonspecific to a more polarized, specific inflammatory response that ultimately leads to the development of adaptive immunity." A BATTLE AGAINST SELF The reason for inflammation's infamy: It shares an intimate relationship with the outside world. "The innate immune system--aside from ... the skin and epithelial barriers that would otherwise interact with the environment--is your first line of defense," explains Randall S. Johnson, associate professor of biological sciences, UC-San Diego. Because it is the first and most aggressive defender, he says, innate immunity can be described as being "on a hair trigger." Centuries ago, this trigger was pulled on a more consistent basis as humans battled a harsher environment; Johnson attributes today's toll of inflammation on the super clean environments of Western society. Also, because humans are living longer than evolutionarily designed, and in larger numbers, says Johnson, the odds are increased for disease. "You have an immune system that's looking for something to do and is basically getting into trouble," he says. "I think the problems are caused by an ongoing, aggravated, chronic response to an immune problem that the innate system imagines is there, but isn't." Also, the various byproducts associated with immune system attack, such as reactive oxygen species that decimate joints, may be causing long-term, deleterious effects. THE ANGIOGENESIS FACTOR Last spring, Johnson and colleagues found that eliminating the ability of white blood cells to respond to low oxygen levels blocks inflammation from developing in mice. This finding eventually could have implications for treating arthritis, other known inflammatory diseases, and some cancers.1 "We were thinking about this process of responding to low-oxygen conditions from the standpoint of tumor biology, because hypoxia releases angiogenic factors," he explains. As a tumor expands, the interior becomes oxygen-deprived because of its decreased blood supply. This situation turns on the hypoxic response pathway, which releases angiogenic factors, and allows blood vessels to move in and alleviate the internal hypoxia. New clinical applications would interrupt that feedback loop, thus exploiting the connection between inflammatory cells, angiogenesis, and tumor growth. Using three new murine knockouts for genes that control a cell's ability to adjust to low-oxygen environments (most notably hypoxia-inducible transcription factor-1, or HIF-1), the researchers found that white blood cells (neutrophils and macrophages) could switch back and forth between an oxygen-dependent and oxygen-independent metabolism. White blood cells outside the blood vessels need to operate in a low-oxygen microenvironment. By preventing the hypoxic response in these cells, inflammation was prevented as well. Specifically, the researchers found that HIF-1 inactivation blocked the inflammatory response in mice. THIN AIR: Hypoxic response pathways mediate inflammation. ... Click for larger version (104K) The notion that a close association exists between inflammation and cancer is not new. Strieter, who works with cytokine biology in inflammation and in promoting angiogenesis, cites ulcerative colitis as one of several examples. "Here we have an autoimmune inflammatory process that's perpetual in nature and is highly associated with the development of colon cancer," he says. Another example is hepatitis, which unlike ulcerative colitis, involves a microbial infection at some point in the host's history and may lead to cirrhosis and hepatomas. "Another example that we as pulmonologists think about in the peripheral of the lung is a tumor that develops in conjunction with a nearby scar, suggesting that at one time there was an inflammatory process," says Strieter. Many of the genes and molecules associated with cancer provide a survival advantage for the tumor itself, including the microenvironment in which the tumor thrives. Also, the host's response to tumor progression involves numerous cells associated with inflammation. "Many of the tumor macrophages are what we would find in any chronic inflammatory process, and they can generate molecules that are important in the perpetuation of those tumor cells," explains Strieter. THE COX CONNECTION A recent line of clinical evidence points to another key link between inflammation and cancer. Randall Harris, a professor in the division of epidemiology and biometrics at Ohio State University, and colleagues followed 81,000 women as part of a 15-year government-sponsored research program called the Women's Health Initiative. They found that nonsteroidal anti-inflammatory drugs (NSAIDs) seem to reduce the risk of breast cancer. In data that was slated to be presented at the American Association for Cancer Research annual meeting, taking aspirin or ibuprofen three or more times a week for five to nine years appeared to reduce the incidence of cancer by 21%; after 10 or more years, the risk reduction was 28%. For ibuprofen alone, the risk was cut by 49% after taking the drug for more than 10 years.2 "The dose [at which] we see effects are standard amounts--200 mg of ibuprofen and 325 mg of aspirin--so we're not talking about heavy doses," comments Harris. These anti-inflammatory agents may target cancer through the COX-2 enzyme, Harris says.3 All NSAIDs, with differing degrees of activity, block COX-2 (see page 31), which triggers inflammation and is overexpressed in most human breast cancers. COX-2 inhibition, he surmises, is linked to cell division and angiogenesis inhibition, as well as reduced mutation rates. COX-2 activation and subsequent proinflam-matory prostaglandin production interferes with cell apoptosis. Furthermore, the chief prosta-glandin E2 stimulates the gene for aromatase, a major enzyme needed for androgen-estrogen conversion, which in turn leads to local estrogen synthesis. "That's important for specificity in breast cancer in this case," says Harris. Andrew J. Dannenberg, director of cancer prevention, New York-Presbyterian Hospital at Cornell University, concurs. "The link between chronic inflammation and cancer is well established," he says. "It's reasonable to postulate that COX-2 is one of the molecules important for mediating the carcinogenic effect." Pharmacologist Trevor Penning, University of Pennsylvania, offers two other mechanisms for the cancer- COX-2 connection that he says are not mutually exclusive. First, activation of prosta-glandins may prevent apoptosis. Second, NSAIDs may work independently of COX-2, increasing the available ligand, prostaglandin J2, for the peroxisome proliferator activating receptor. This antiproliferative effect has been observed recently in human leukemia cells, Penning says. The next step, Harris says, is to look at the selective COX-2 blockers. When the Women's study concluded, the US Food and Drug Administration had not yet approved Celebrex and Vioxx, the two COX-2- specific inhibitors that are now used commonly to treat arthritic conditions. AD, A MATTER OF RESPONSE ApoE4 is the only well-established genetic risk factor for AD, notes John Q. Trojanowski, director of the University of Pennsylvania Alzheimer's Disease Center. "This is the big conundrum: How does apoE4 cause the disease?" The apoE4 allele is associated with abundant amyloid plaques. Some researchers think that extracellular plaque bumps into inflammatory cells of the nervous system, such as microglia, thus eliciting the inflammatory re-sponse. "It is clear that inflammation is part of Alzheimer disease," says Trojanowski, especially through concomitant oxidative damage. "But it's not so clear what apoE4 does in this process." And that, says Crutcher, brings up the lack-of-definition situation. "I think one of the problems in this area is that no one can agree as to what they mean by inflammation," he says. "If you take the broadest definition of inflammation, which is a tissue-specific response for infection, then I am all onboard [with saying] something like Alzheimer almost certainly involves some aspect of inflammation." A PRECARIOUS BALANCE: Development of an appropriate innate host response in the lung requires the recognition of microbial molecular patterns by the toll like receptors (TLRs) ... Click for larger version (55K) Crutcher and colleagues have presumed that apoE plays a direct rather than secondary role in AD pathology. "ApoE is at least guilty by association and our own work suggests that, at least in reduced tissue culture systems, apoE can kill neurons," says Crutcher. Another way to approach this is to think about inflammation as a response, he adds. "Then any number of diseases can be characterized as diseases of response," including Alzheimer. For example, he says head injuries appear to increase the risk of AD developing, and other data suggest that a prior herpes simplex infection might be a risk factor for AD. BUGS AND GASTRIC CANCER That pathogens may elicit a disease caused by the human response is also nothing new. The bacterium H. pylori can induce gastritis in some people, and has been classified since 1994 as a definite human carcinogen by the International Agency for Research on Cancer in Lyon, France. El-Omar found that some people are genetically predisposed to stomach cancer, especially if they have a genetic polymorphism for hyperproduction of the cytokine interleukin-1 b.4 This proinflammatory phenotype leads to a neutral pH in the stomach, which is favorable to H. pylori and other bacteria, and eventually cancer. Last year, Thomas Borén, Department of Odontology/Oral Microbiology, Umeå University, Sweden, and colleagues, including molecular microbiologist Douglas Berg, Washington University in St. Louis, explained how H. pylori infection can be so tenacious. As inflammation due to H. pylori infection proceeds, the cells of the stomach lining display sialyl Lewis x (sLex), a carbohydrate previously identified as a tumor antigen and a marker for gastric dysplasia. This carbohydrate, which is not displayed in healthy stomach cells, generally attracts immune cells. H. pylori also latches on to sLex, however, allowing the bacteria to be pulled in closer to the stomach cells, where they presumably find food. Inflammation increases for a time, but then the wary bacteria move away from the stomach cells to avoid being destroyed by the incoming immune cells.5 This back-and-forth movement, and the bacteria's ability to adjust its adherence properties, could explain the persistent ebb and flow in gastritis flare-ups. "Helicobacter bacteria are pretty clever; they have been able to adapt to these conditions," says Borén. Perhaps scientists could learn from these clever bacteria to inevitably control and subdue, or at least rein in, the inflammatory response before damage is done. This could certainly make inroads into understanding disparate, yet well known human ailments. Karen Kreeger (kykreeger@aol.com) is a freelance writer in Media, Pa. References 1. T. Cramer et al., "HIF-1alpha is essential for myeloid cell-mediated inflammation," Cell, 112:645-57, 2003. 2. R.E. Harris et al., "Inverse association of breast cancer and NSAIDs: Results from the Women's Health Initiative (WHI)," Proc AACR, vol. 44, March 2003. 3. R. Harris, ed., COX2 Blockade in Cancer Prevention and Therapy, Totowa, NJ: Humana Press, 2002. 4. E. El-Omar et al., "Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms," Gastroenterol, 124:1193-201, 2003. 5. J. Mahdavi et al., "Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation," Science, 297:573-8, 2002 function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

Inflammation's infamy

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Courtesy of Keith Crutcher
IMMUNITY IN MIND: Cultured microglial (N9) cells (red) on a tissue section containing an Alzheimer plaque (green). There is continuing controversy about whether these types of inflammatory cells are responding to plaques or causing them.