Molecular and Cellular Physiology of Acute Inflammatory Cytokines 
the degree of cellular injury and cause greater 
release of LDH. Conversely, agents that reduce 
IL-1 release either reduce IL-1 synthesis or en- 
hance cell viability. 
Although the release of IL- 1 from IL- 1 -produc- 
ing cells is not via a specific release pathway, the 
outcome of release can be modulated. This is 
demonstrated by studies in which IL-1 -produc- 
ing cells are deliberately injured. In the most gen- 
eral terms, there are two types of cellular injury. 
One type occurs when vital cellular functions are 
interrupted, leading to cellular necrosis. This oc- 
curs as a consequence of many stress injuries, in- 
cluding hypoxia, alterations in local pH, ex- 
tremes of temperature, and physical attack by 
infectious lytic viruses. Morphologically, ne- 
crotic cells exhibit disruptions in their plasma 
membrane and disintegration of the intracellular 
organelles. The consequence of necrosis is the 
release into the extracellular space of all of the 
soluble cellular components. As expected, when 
an IL-1 -producing cell sustains a necrotic injury, 
the IL- 1 precursors are released along with all of 
the other cellular components; however, there is 
failure of processing of the IL-1|8 precursor to its 
mature form. This failure is important, because 
maturation is required for the IL-l/? precursor to 
acquire receptor-binding activity (and, conse- 
quently, for the acquisition of all of the known 
IL-1 functional activities). 
In contrast to cellular necrosis, cell death can 
occur in a regulated fashion. Normal develop- 
ment and tissue remodeling frequently require 
removal of otherwise viable cells. This occurs by 
activating the pathway of programmed cell death 
leading to apoptosis. Morphologically, apoptosis 
is very different from necrosis, with apoptotic 
cells showing retention of the integrity of their 
plasma membranes and maintenance of the struc- 
ture of intracellular organelles. Portions of the 
cell are released as membrane-coated blebs and 
are subsequently ingested by phagocytic cells 
and digested. Apoptosis permits the termination 
of the life of a cell with minimal release of cellu- 
lar debris into the extracellular environment. 
This pathway is activated during many stages of 
embryological development and to initiate nor- 
mal cell turnover. In the immune system, re- 
moval of self-reactive T lymphocytes in the thy- 
mus occurs by apoptosis, as does the death of 
target cells attacked by cytotoxic lymphocytes. 
When this pathway of programmed cell death is 
activated in macrophages expressing the IL-1 
precursors, there is striking, rapid, and complete 
maturation and release of both forms of IL- 1 . 
Thus, in cells expressing only IL-l/? (such as 
blood monocytes and certain cells in the spleen 
and thymus), apoptosis — in contrast to necrosis 
— affords an efficient method for generating 
bioactive IL-1 . 
These results have given us a new appreciation 
of IL-1 as a physiological signal of cell and tissue 
injury. IL- 1 does not appear to be released from 
the cell that produces it unless a significant cell 
injury occurs. If the injury is necrotic in nature, 
then IL-1/3 is released in only its inactive precur- 
sor form. If, on the other hand, the injury leads to 
apoptosis, then mature bioactive IL-1/3 is released 
in a form ready to activate the systemic responses 
that lead to tissue repair. 
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