Biology Reference
In-Depth Information
[81]
. Thus, the final tissue response to HMGB1 is the result of a complex network
of interactions among several signaling molecules, relevant receptors engaged, and
different sensitive cell types. A number of important parameters converge to deter-
mine a protective or a detrimental response, including the effective concentrations of
cytokines and chemokines involved, the duration of these stimuli, and their capability
to interact with each other in a synergistic or antagonistic manner.
3.4 Conclusion
Early studies on the extracellular signal properties of HMGB1 indicated that this
protein is a potent immediate and late mediator of inflammation
[6,12]
. However,
experimental evidence reported in this review, and in other recent reports, supports the
assumption that HMGB1 behaves as a key regulator of CNS functions, but indicate
that it is not endowed with classical pro-inflammatory properties both in
in vitro
and
in vivo
conditions
[22,58]
. This discrepancy can be attributed to the remarkable abil-
ity of HMGB1 to interact with several unrelated protein molecules, resulting in the
formation of protein complexes that acquire new signaling properties. Specifically, it
has been shown that the high inflammatory activities previously attributed to HMGB1
could be due to a highly enhanced pro-inflammatory function displayed by IL-1 and
IFN- bound to HMGB1
[35]
. Hence, we know that HMGB1 can directly activate dif-
ferent cell programs, depending on the specific receptors expressed and on the intra-
cellular cascades involved, but it can also amplify inflammatory responses through
binding to pro-inflammatory mediators. An emerging field of research is aimed to shed
light on the molecular mechanisms that modulate the inflammatory processes in the
CNS. Exploration of the involvement of HMGB1 in specific physiopathological con-
ditions is needed if we are to understand the contribution of this cytokine in neuroin-
flammation, neurological disorders, and postischemic damage, as well as in regulation
of the neuroimmune system. Moreover, the potential roles of HMGB1 as an inducer of
tissue reparation in mild acute inflammatory diseases, and also as a mediator of dam-
age in chronic inflammatory conditions, pose several challenging questions about the
possibility of exploiting this versatile cytokine as a target of new therapeutic strategies.
Acknowledgments
This work was supported by University of Genoa 2008 and Italian Ministry of
University and Research (PRIN 2008) grants to BS.
References
1. Goodwin GH, Johns EW. The isolation and purification of the high mobility group (HMG)
nonhistone chromosomal proteins. Methods Cell Biol 1977;16:257-67.
