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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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