Molecular Inflammation

Much of the physiology of inflammation is the response of tissue to injury. At the cellular level, inflamed tissues express a particular set of five dozen inflammatory genes. Several different inputs can trigger inflammation, but a single transcription factor, NFkB, turns on the inflammatory gene program.

Each tissue has unique structures and functions as a result of different proteins, yet essentially all cells have the same genes. The differences are due to the expression of subsets of the total 20,000 or so genes -- each different type of cell produces different amounts of protein from each of the available genes. The history of each cell, its cellular neighbors and the biochemical signals that it has received, determines how genes are expressed by the presence or absence of the master molecular controls, the transcription factors. These control proteins interact by sticking to the control sequences at the end of the DNA sequences that are the genes along the very long DNA molecules called chromosomes. Humans have 64 chromosomes -- 23 pairs and on average each chromosome has about a thousand genes interspersed among long stretches of other DNA. The point here is that a particular protein can bind to part of a group of genes, the control region, and the designated genes will be turned on to produce the proteins of inflammation.

The transcription factor that controls inflammation is nuclear factor kappa B, NFkB. Its name reflects its initial characterization in B lymphocytes that were stimulated to produce the heavy chain of immunoglobulins, the kappa chain. NFkB was ultimately implicated in the control of the expression of many genes integral to immunity and that included the suite of genes characteristic of inflammation.

Transcription factors, such as NFkB, physically stick to particular sequences of the four DNA bases, ATG or C, and this means that the NFkB protein has positively charged (basic, i.e. arginine or lysine) amino acids that hydrogen bond with the negatively charged phosphate groups of the DNA. This general interaction is similar to the binding of extracellular proteins to heparin. Moreover, the proteins that interact with DNA or RNA are all found in the nucleus, so it is not surprising that all of the nuclear proteins have a nuclear localization signal, NLS, that in most cases consists of groups of basic amino acids (BBBB or BBxxxx...xxxBB) that are also classes of heparin binding domains. Proteins with these NLSs exposed will be transported from the cytoplasm to the nucleus and if present extracellularly, they will be endocytosed by binding to heparan sulfate proteoglycans and then transported to the nucleus. I think that these unusual properties are the basis for why extreme autoimmune diseases, such as lupus, result in the production of antibodies against nuclear proteins.

The genes turned on for expression by NFkB when inflammation is triggered yield the inflammatory cytokines, IL-1, IL-6 and TNF; the enzyme that makes omega-3 and omega-6 fatty acids into the corresponding anti-inflammatory and inflammatory prostaglandins, COX-2; and the enzyme producing nitric oxide, iNOS. You may notice that many of these protein products can in turn also stimulate inflammation and they can in fact cause the spread of inflammation in a radiating wave from the point of initiation. As this wave encounters the dendrites of neurons, pain can result, but additional signals are transmitted to the brain and the response down the vagus nerve produces the regional production of anti-inflammatory cytokines that control the continued spread of inflammation.

Many plant products bind to proteins involved in the signaling of inflammation. Aspirin for example binds to COX-2 and stops the production of prostaglandins. The inflammatory prostaglandins are needed for the proper development of stomach lining, so aspirin in high local concentrations can damage the gut. Since COX-2 is needed for anti-inflammatory prostaglanding production it also has this negative result. Aspirin also binds directly to NFkB and in so doing blocks inflammation directly. The turmeric compound, curcumin, is even more effective at blocking inflammation by interacting with NFkB. Unfortunately curcumin is “detoxified” by enzymes in the intestines and its inflammatory actions are thereby diminished. The cultural practice of including black pepper with turmeric compensates for the gut effects, because the piperine in black pepper inactivates the defensive enzymes and temporarily permits serum levels of curcumin to become therapeutic.