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Page 4 of 10 Yang et al. Plast Aesthet Res 2020;7:34 I http://dx.doi.org/10.20517/2347-9264.2020.24
[4]
(NE, E) increased IL-6 expression and increased resistance in NSCLC patients . Therefore, we hypothesize
that the psychological stress (NE, E) might stimulate keloid pathogenesis by enhancing IL-6 expression
via activating β-ARs, and the use of β-blockers such as propranolol might facilitate the efficacy of current
keloid treatments.

IL-6 is one of the Th1 type cytokines related to pro-fibrosis and inflammation [16,17] , which has been regarded
as a marker of keloid progression. A significant increase of IL-6 and IL-6 signaling elements was observed
[7]
in keloid fibroblasts (KFs) compared to normal fibroblasts (NFs) . Moreover, the induction of IL-6 by IL-6
peptide in NF cultures or inhibition of IL-6 or IL-6Ra by their corresponding antibodies in KF cultures
rendered a dose-dependent increase or decrease in the synthesis of collagen type I . This was possibly the
[7]
result of the suppression of matrix metalloproteinases (MMPs) at mRNA level and pro-matrix MMPs at the
[18]
protein level . Besides, a Japanese population-based study involving IL6R genotypic and allelic analyses
among 239 normal and 376 keloid patients revealed that the IL-6 572G/C polymorphism is associated with
[19]
susceptibility to keloid formation and the severity of keloid scarring .

Multiple stress models have confirmed that a higher plasma level of IL-6 was also observed in people
with depressive symptoms or at a stressed state (for example, angry couples after a domestic conflict or
vaccination with an influenza virus vaccine) [20,21] , suggesting a stress hormone (NE, E)-mediated IL-6
augmentation.

The importance of psycho-physiological interactions has gained increasing attention recently, and NE-
induced IL-6 elevation has been taken as a predictor of treatment resistance and poor outcomes in
certain cancers. For example, researchers found that by binding to β2-ARs, stress hormones (NE, E) can
subsequently induce IL-6 expression via suppressing liver kinase B1 and activating cAMP-responsive
element-binding protein. Therefore, Combinational treatments with propranolol (β-AR inhibitor) could
effectively lower the IL-6 concentration and prolong the progression-free survival in EGFR TKIs resistant
[4]
patients . Apart from lung cancers, it was also observed that the NE/E induced activation of ARs also
resulted in a similar increase of IL-6 in ovarian cancer cells .
[5]

The β-ARs have been suggested as potential pharmacologic targets of catecholamine actions that influence
numerous physiological and metabolic activities systemically in human bodies [22,23] . Both in vitro and in vivo
studies of β-ARs carried out over the past decades focused mainly on their effects on cardiac function,
whereas reported studies on non-cardiac β-blocker effects focused on their roles in the wound healing
[22]
process . Propranolol is a representative nonselective β-adrenergic blockade agent with promising
efficacy in rhythm disturbances and hypertension. It was found that in propranolol-treated animals, wound
contraction and the formation of the neo-epidermis and granulation tissue were delayed . de Mesquita
[24]
[22]
hypothesized that systemic or intralesional injection of propranolol could serve as a novel cure of
keloids because of its potential to induce vasoconstriction in over-proliferating tissues, trigger apoptosis
of endothelial cells, and modulate inflammatory process during wound healing. Moreover, one single-
institution case-control study in 2017 also observed better scar formation in post-surgery patients who
[25]
were administrated with β blockers . It is noteworthy that patients with abnormal scar histories or family
tendency are excluded in this study, and the administration of other hypertension drugs such as calcium
channel blockers showed no association with the scar quality, a phenomenon that indirectly supports our
hypothesis that adrenergic activation might be an independent risk factor for the pathogenesis of keloid
[25]
and hypertrophic scars . Noticeably, yearlong administration of oxandrolone and propranolol successfully
reduced scar severity and pliability in the -post-burn hypertrophic scar patients and their emotional
[26]
health state was also improved . Encouraged by the findings of the propranolol-based study showingthe
reduction in NE-induced IL-6 elevation with an altered prognosis of NSCLC patients and the studies
outlined above, we strongly propose that it might be promising to use propranolol for targeting β-ARs on
keloid cells to disrupt IL-6 mediated keloid pathogenesis.