Page 78 - Veterinary Immunology, 10th Edition

microbes. It attracts neutrophils to sites of tissue damage and
VetBooks.ir increases their adherence to vascular endothelium. It stimulates

macrophage phagocytosis and oxidant production. It amplifies and
prolongs inflammation by promoting macrophage synthesis of
important enzymes such as nitric oxide synthase and

cyclooxygenase, and it also activates mast cells. TNF-α induces
macrophages to increase its own synthesis together with that of IL-
1. As its name implies, TNF-α can kill some tumor cells as well as

virus-infected cells. In high doses, TNF-α may cause septic shock
(Chapter 7). It mediates all these actions through two receptors:
TNFR1 is found on many different cells, where it can bind both
soluble and membrane-bound TNF-α; and TNFR2 is restricted to
the cells of the immune system and responds only to membrane-

bound TNF-α.
TNF-α is a member of a family of related molecules. Important
members of this family include TNF-β (or lymphotoxin) (Chapter

19); CD40L (Chapter 20); and FasL (CD95L) (Chapter 18).

Interleukin-1

When stimulated through CD14 and TLR4, sentinel cells such as
macrophages also synthesize cytokines belonging to the

interleukin-1 family. The most important of these are IL-1α and IL-
1β. IL-1β is produced as a large precursor protein that is cleaved by
caspase-1 to form the active 17.5-kDa molecule. Ten- to 50-fold
more IL-1β is produced than IL-1α, and whereas IL-1β is secreted,
IL-1α remains attached to the cell surface. As a result, IL-1α only

acts on cells that directly contact macrophages (Fig. 3.2).
Transcription of IL-1β messenger RNA (mRNA) occurs within 15
minutes of ligand binding. It reaches a peak 3 to 4 hours later and

levels off for several hours before declining. Like TNF-α, IL-1β acts
on nearby cells to initiate and amplify inflammation. For example, it
acts on vascular endothelial cells to make them adhesive for
neutrophils. IL-1 also acts on macrophages to stimulate their
synthesis of NOS2 and COX-2.

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