Inflammatory Response Pathway

Inflammation is a protective response of cells to pathogens, infection or tissue damage. It involves the coordinated communication of different immune cells and blood vessels through an intricate cascade of molecular signals. Inflammation can cause fever, cardiovascular pathology, allergy anaphylaxis, fibrosis, autoimmunity, etc.

The inflammatory response has four phases: inflammatory inducers (infection or tissue damage), inflammatory sensors (mast cells and macrophages), inflammatory mediators (cytokines, chemokines, etc.) and the tissues that are affected ^[3]. Each phase has many options that are triggered based on the type pathogen introduced ^[1]. For example bacterial pathogens trigger toll-like receptors (TLRs) and viral infections trigger type I interferons (IFN) ^[3].

In addition, chronic inflammatory conditions, where an inducer is not well defined, are becoming more common. These conditions are of particular interest because they coincide with other diseases such as obesity, type 2 diabetes, atherosclerosis, neurodegenerative diseases and cancer ^[3,4,5].

Thermo Scientific™ has a wide range of products to help with inflammatory response research.

Common targets in the inflammatory response pathway:

Three common transcription factors serve as key modulators in the inflammatory response pathway – nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), hypoxia-inducible factors-1 alpha (HIF-1α) and signal transducer and activator of transcription (STAT) . When inflammation becomes chronic these factors can lead to cancer ^[5]. 

NF-κB functions as the regulator of the acute phase of inflammation. The acute phase is where homeostasis is re-established after inflammatory induction. NF-κB acts by up regulating the expression of the cytokines that are inflammatory mediators. These cytokines include IL-1, IL-6, TNF-α, lymphotoxin and IFN-γ. In addition, IL-1 and TNF-α work to activate NF-κB, therefore creating a feedback loop ^[2].

HIF-1α plays a role in the cellular response to hypoxia. When oxygen levels decrease, HIF-1α induces transcription of genes that control processes such as angiogenesis and erythropoiesis. During inflammation, immune cells in the surrounding area experience a decrease in oxygen.  This decrease activates HIF1-α to help them survive longer. A number of cytokines, for example IL-1β, help HIF-1α to increase transcription. The use of the cytokines is mediated through NF-κB, which is shown to bind to HIF-1α promoters ^[6].

The STAT family of proteins serves multiple functions during inflammation depending on the type of inflammatory inducer. The type of inducer determines which cytokines are triggered. Those cytokines activate a STAT protein, which either increases or decreases inflammation. For instance, when the body comes into contact with a viral infection various IFNs are triggered and activate STAT1 and STAT2 that act in an anti-viral capacity to decrease inflammation. In contrast, STAT6 helps with differentiation of T helper cells. Subject to the type of differentiation, the T helper cells can positively influence allergic inflammation and negatively affect autoimmunity ^[7].

1. Medzhitov R. (2008) Origin and physiological roles of inflammation. Nature 454: 428-435.
2. Ghosh S. et al (1998) NF-κB and rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16: 225-260.
3. Medzhitov R. (2010) Inflammation 2010: new adventures of an old flame. Cell 140: 771-776.
4. Bharat B. et al (2009) Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 15(2): 425-430.
5. Chiara P. et al (2009) Cellular and molecular pathways linking inflammation and cancer. Immunobiology 214(2009): 761-777.
6. Scholz C. et al (2013) Targeting the HIF pathway in inflammation and immunity. Current Opinion in Pharmacology 13: 646-653.
7. Kaplan, M. (2013) STAT signaling in inflammation. JAK-STAT 2: 1.