Biology Reference
In-Depth Information
Chapter 3
Tissue-Protective Cytokines: Structure and Evolution
Pietro Ghezzi and Darrell Conklin
Abstract
Cytokines are important mediators of host defense and immunity, and were first identified for their role in
immunity to infections. It was then found that some of them are pathogenic mediators in inflammatory
diseases and much of the emphasis is now on pro-inflammatory cytokines, also in consideration of the fact
that TNF inhibitors became effective drugs in chronic inflammatory diseases. The recent studies on the
tissue-protective activities of erythropoietin (EPO) led to the term “tissue-protective cytokine.” We dis-
cuss here how tissue-protective actions might be common to other cytokines, particularly those of the
4-alpha helical structural superfamily.
Key words
Helical cytokines, Hematopoietic cytokines, 3D structure, Evolution, Host defense
1
Tissue-Protective Cytokines in the Context of Host Resistance
Surviving an infection is achieved in two ways: resistance (reducing
the number of pathogens, such as by innate or adaptive immunity)
and tolerance (surviving the damage produced by the pathogen),
as outlined in Fig.
1
. Read et al. (
1
) recently suggested that “dam-
age control may be more important than pathogen control,” and
the underlying mechanisms can probably be implicated in tissue
damage non-necessarily associated with infections (
2
).
Initially, cytokines were identified in an effort to characterize the
effectors of “pathogen control,” with a focus on the antiviral and
anticancer activity of the immune system (
3
). The idea was that these
effector cytokines could be used as drugs. This led to the discovery
of interferons, interleukins 1 and 2, and TNF. However the real
impact in terms of “translational medicine” came from the discovery
of the pro-inflammatory actions of TNF (
4
) and IL-1 (
5
), with the
finding that cytokines produced by the immune system in response
to infection can also cause inflammation and tissue damage. The
enormous impact of this paradigm-shifting concept is demonstrated
by the fact that TNF inhibitors (anti-TNF antibodies and soluble
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