The local inflammatory response is accompanied by a systemic response known as the acute-phase response (Figure 15-13). This response is marked by the induction of fever, increased synthesis of hormones such as ACTH and hydrocortisone, increased production of white blood cells (leuko-cytosis), and production of a large number of acute-phase proteins in the liver. The increase in body temperature inhibits the growth of a number of pathogens and appears to enhance the immune response to the pathogen.
C-reactive protein is a prototype acute-phase protein whose serum level increases 1000-fold during an acute-phase response. It is composed of five identical polypeptides held together by noncovalent interactions. C-reactive protein binds to a wide variety of microorganisms and activates complement, resulting in deposition of the opsonin C3b on the surface of microorganisms. Phagocytic cells, which express C3b receptors, can then readily phagocytose the C3b-coated microorganisms.
Many systemic acute-phase effects are due to the combined action of IL-1, TNF-a and IL-6 (see Figure 15-13). Each of these cytokines acts on the hypothalamus to induce a fever response. Within 12-24 h of the onset of an acute-phase inflammatory response, increased levels of IL-1, TNF-a and IL-6 (as well as leukemia inhibitory factor (LIF) and onco-statin M (OSM)) induce production of acute-phase proteins by hepatocytes. TNF-a also acts on vascular endothelial cells and macrophages to induce secretion of colony-stimulating factors (M-CSF, G-CSF, and GM-CSF). These CSFs stimulate hematopoiesis, resulting in transient increases in the number of white blood cells needed to fight the infection.
The redundancy in the ability of at least five cytokines (TNF-a, IL-1, IL-6, LIF, and OSM) to induce production of acute-phase proteins by the liver results from the induction of a common transcription factor, NF-IL6, after each of these cytokines interacts with its receptor. Amino-acid sequencing of cloned NF-IL6 revealed that it has a high degree of sequence identity with C/EBP, a liver-specific transcription factor (Figure 15-14a). Both NF-IL6 and C/EBP contain a leucine-zipper domain and a basic DNA-binding domain, and both proteins bind to the same nucleotide sequence in the promoter or enhancer of the genes encoding various liver proteins. C/EBP, which stimulates production of albumin and transthyretin, is expressed constitutively by hepatocytes. As an inflammatory response develops and the cytokines interact with their respective receptors on liver hepatocytes, expression of NF-IL6 increases and that of C/EBP decreases (Figure 15-14b). The inverse relationship between these two transcription factors accounts for the observation that serum levels of proteins such as albumin and transthyretin decline while those of acute-phase proteins increase during an inflammatory response.
Was this article helpful?
This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.