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endothelial cells and smooth muscle cells. Strikingly, during
inflammatory states, these cell types are known to be major target
cells of IL-6 (
11
).
2
IL-6 Classic and Trans-signaling
Several years ago, it was found that membrane-bound IL-6R can
be proteolytically released by cells thereby leading to the genera-
tion of a soluble IL-6R (sIL-6R) (
12, 13
). Alternatively, human
cells have been shown to translate the IL-6R from an alternatively
spliced mRNA lacking the coding region for the transmembrane
domain, thereby also leading to the release of sIL-6R. Interestingly,
in the mouse, no alternative splicing of the IL-6R mRNA has been
detected. In humans, the release of sIL-6R has been shown to
occur in a circadian rhythmical fashion and the increase of sIL-6R
during the night has been shown not to be due to the alternative
splicing of IL-6R mRNA (
14
). It has been concluded that the reg-
ulated release of sIL-6R is regulated by the proteolytic cleavage
rather than by an alternative splicing (
15
). The major protease
responsible for shedding of IL-6R has been identified to be the
membrane-bound metalloprotease ADAM17 (
15-19
). Interestingly,
ADAM17 has also been identified as the protease responsible for
cleavage of the membrane-bound cytokine Tumor Necrosis Factor
alpha (TNF
) (
20, 21
).
It turned out that on cells, which do not express IL-6R and
which therefore cannot be stimulated by IL-6, the complex of IL-6
and sIL-6R can bind to gp130, induce dimerization and subse-
quent signaling (Fig.
1
). This process has been called trans-signal-
ing (
10
). IL-6 signaling via the membrane-bound IL-6R is called
classic signaling. Conceptually, by generating sIL-6R, one cell ren-
ders a distinct cell responsive to the cytokine IL-6 (
7, 8, 10, 22
).
In a molecular model of the complex of IL-6 and sIL-6R, the
NH
2
-terminus of IL-6 is 40 Å from the COOH-terminus of sIL-
6R (
23, 24
). Consequently, on the cDNA level, we generated a
fusion protein of IL-6 and sIL-6R in which the two proteins were
connected via a peptide linker of flexible amino acids, which was
long enough to bridge the 40 Å. The resulting fusion protein was
called Hyper-IL-6 (Fig.
2a
) (
25
). This protein turned out to be a
molecular tool that identifies cells in vitro and in vivo, which, in
their response to IL-6, depended on sIL-6R. It turned out that
hepatocytes (
26, 27
), neural cells (
28, 29
), neural stem cells (
30
),
smooth muscle cells (
31
), hematopoietic progenitor cells (
32-38
),
and embryonic stem cells (
39, 40
) require sIL-6R in their full
response to IL-6.
Since IL-6 does not directly bind to gp130, a soluble version
of gp130 (sgp130) was not found to interfere with classic signaling
via the membrane-bound IL-6R, but to specifically inhibit IL-6
α
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