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In-Depth Information
Table 3
Studies with knockout mice showing a protective role of cytokines
Cytokine
Cell target
End-point
Reference
IL-6
Neuron
Trimethyltin neurotoxicity
(
101
)
IL-6
Brain
Cortical freeze lesion
(
108
)
IL-6
Wound healing
(
109
)
GM-CSF
Ko in non-hematopoietic cells
Increased NSAID ileal injury
(
110
)
GM-CSF
Impaired skin wound healing
(
111
)
2
4-Alpha-Helical Cytokines
Helical cytokines form a structurally conserved family with all
members containing a structurally conserved four helices, by con-
vention labeled A through D, in a four-helix bundle. As with all
soluble helix bundle proteins, the helices are amphipathic, having
a solvent-facing hydrophilic side and a buried hydrophobic side.
The distinguishing factor of what may be called the helical cytokine
fold is the particular topological layout of helices; they are always
in an up-up-down-down orientation, unlike any other known
helix bundle fold.
In addition to the distinctiveness of their helix bundle fold
topology, further evidences for the common evolutionary origins
of helical cytokines is in their gene structures, which in cases conserve
the number of exons and intron phase patterns. Despite containing
a common structural core and having evolutionary origins, the
helical cytokines exhibit a diverse variety of features (
40
), including
the type of receptor they bind (
43
), their number of exons and
intron phase patterns (
44
), whether they are short or long chain
(the long chain cytokines having longer helices than the short
chain), whether they bind their receptor through monomers,
homodimers, or heterodimers, and a further topoisomeric feature
where the loop between helices B and C threads over or through
the loop between helices A and B. Furthermore they can be grouped
into four categories based on the structure of their preprotein
sequence (see (
40
) for details): the presence (groups 1, 3, 4) or
lack (group 2) of a signal peptide, the presence of C-terminal
hydrophilic sequence that is released by extracellular proteases
(group 3) or alternatively a transmembrane domain C-terminal of
the helix bundle (group 4).
Thus the discovery or verification of new members of this fam-
ily is difficult due to the lack of sequence homology between mem-
bers of different homology groups. The standard BLAST method
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