Beta-adrenergic stimulation of cyclic AMP is defective in cultured dermal fibroblasts of psoriatic subjects

Eedy, D.J.; Canavan, J. P.; Shaw, Christopher; Trimble, E.R.

doi:10.1111/j.1365-2133.1990.tb14724.x

Cited by 17 publications

(13 citation statements)

References 38 publications

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“…This could support recent observations that CyA and perhaps also FK 506 influence not only immunocom petent cells but also kératinocytes in the treat ment of this disease. Our results agree with those investigators postulating that the induc tion of cAMP is probably a positive mitogenic and morphogenic signal required for the in duction of cell growth and differentiation [28,31,34,35,37]. Since immunosuppressive drugs reduced the cAMP level in psoriatic kératinocytes, it is very doubtful that low lev els of cAMP should be a trigger for the epider mal hyperproliferation in psoriasis.…”

Section: Discussionsupporting

confidence: 78%

“…How ever, in contrast to the findings of Eedy et al [28], we did not detect differences in the cAMP stimulation of kératinocytes derived from psoriatics compared with those derived from controls. In contrast to an old opinion that only physiological or low levels of cAMP are positive regulators of cell growth and dif ferentiation and could be responsible for hy perproliferation of kératinocytes as seen in psoriasis [12,29,30], recent investigations indicate that elevated cAMP levels initiate the proliferation of a number of eukaryotic cells, e. g. kératinocytes and lymphocytes [17,[31][32][33][34][35], An increase in cAMP has been shown to induce the transcription of different genes, involving the activation of the cAMP-response-element-binding protein and the c-fos and c-myc mRNA expression [33,35], Fur thermore, it could be demonstrated that the 11-2 and IFN-y production was enhanced after activating the catalytic subunit Ca of the pro tein kinase A [36], Therefore, inhibition of cAMP formation followed by a decrease in protein kinase A activity may decrease lym phokine synthesis and secretion.…”

Section: Discussioncontrasting

confidence: 57%

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The Effect of Cyclosporin A and FK 506 on the cAMP Content in Psoriatic Keratinocytes

Ockenfels¹,

Nussbaum²,

B³

et al. 1996

Skin Pharmacol Physiol

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FK 506 and cyclosporin A (CyA) are two immunosuppressive drugs which are known to be effective in the treatment of psoriasis by inhibiting the activation of T cells. In contrast, their influence on the proliferation of keratinocytes is discussed controversially. The second messenger cyclic adenosine monophosphate (cAMP) has been regarded as a regulator for cell growth and proliferation for 20 years. Hyperproliferation of many cells and particularly of psoriatic keratinocytes was speculated to be due to a decrease in cAMP levels in the psoriatic epidermis, whereas new findings could not confirm these observations. To clarify this discussion we determined the intracellular cAMP content in isoprenaline-stimulated keratinocytes from psoriatics and controls after treatment with CyA or FK 506. Ethanol and the Β-blocking drug propranolol served as controls. The basal level of cAMP and the response to isoprenaline in psoriatic keratinocytes did not differ from those of controls. CyA dramatically reduced the cAMP level and FK 506 just slightly diminished it in a dose-dependent manner. Both drugs diminished the cAMP level more effectively in the keratinocytes from lesional psoriatic skin than in keratinocytes from controls. These data provide evidence that CyA influences early signal transduction pathways by depressing the intracellular cAMP in keratinocytes. This supports the view of other groups that CyA and perhaps also FK 506 influence not only immunocompetent cells but also keratinocytes in the treatment of psoriasis. Furthermore, it is doubtful that a low cAMP level is a positive regulator for cell growth and the hyperproliferation of psoriatic keratinocytes.

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Section: Discussionsupporting

confidence: 78%

Section: Discussioncontrasting

confidence: 57%

The Effect of Cyclosporin A and FK 506 on the cAMP Content in Psoriatic Keratinocytes

Ockenfels¹,

Nussbaum²,

B³

et al. 1996

Skin Pharmacol Physiol

View full text Add to dashboard Cite

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“…In atopic eczema there is a point mutation in the ␤2-AR gene and a low ␤2-AR density on keratinocytes and peripheral blood lymphocytes (Schallreuter, 1997). In psoriasis, epidermal cells from psoriatic lesions demonstrate a low cAMP response to ␤2-AR activation (Eedy et al, 1990). Additionally, a paracrine role for the hormone mediator network in skin homeostasis has been demonstrated recently as keratinocyte catecholamine synthesis can regulate melanogenesis in melanocytes (Gillbro et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The β2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms

Pullar

Isseroff

2006

Journal of Cell Science

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Dermal fibroblasts are required for skin wound repair; they migrate into the wound bed, proliferate, synthesize extracellular matrix components and contract the wound. Although fibroblasts express ␤ ␤2-adrenergic receptors (␤ ␤2-AR) and cutaneous keratinocytes can synthesize ␤ ␤-AR agonists (catecholamines), the functional significance of this hormonal mediator network in the skin has not been addressed. Emerging studies from our laboratory demonstrate that ␤ ␤2-AR activation modulates keratinocyte migration, essential for wound re-epithelialization. Here we describe an investigation of the effects of ␤ ␤2-AR activation on the dermal component of wound healing. We examined ␤ ␤2-AR-mediated regulation of biological processes in dermal fibroblasts that are critical for wound repair: migration, proliferation, contractile ability and cytoskeletal conformation.We provide evidence for the activation of at least two divergent ␤ ␤2-AR-mediated signaling pathways in dermal fibroblasts, a Src-dependent pro-migratory pathway, transduced through the epidermal growth factor receptor and extracellular signal-regulated kinase, and a PKAdependent pro-proliferative pathway. ␤ ␤2-AR activation attenuates collagen gel contraction and alters the actin cytoskeleton and focal adhesion distribution through PKAdependent mechanisms. Our work uncovers a previously unrecognized role for the adrenergic hormonal mediator network in the cutaneous wound repair process. Exploiting these divergent ␤ ␤2-AR agonist responses in cutaneous cells may generate novel therapeutic approaches for the control of wound healing.

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“…Keratinocytes derived from patients with atopic eczema display a point mutation in the ␤2-AR gene and a low ␤2-AR density (7). In psoriasis, keratinocytes within the psoriatic lesions demonstrate a low cAMP response to ␤2-AR activation (8). These findings point to a role for the ␤2-AR in maintaining epidermal function and integrity.…”

Section: ␤-Adrenergic Receptors (␤-Ars)mentioning

confidence: 83%

β-Adrenergic Receptor Antagonists Accelerate Skin Wound Healing

Pullar

Rizzo

Isseroff

2006

Journal of Biological Chemistry

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The skin is our primary defense against noxious environmental agents. Upon injury, keratinocytes migrate directionally into the wound bed to initiate re-epithelialization, essential for wound repair and restoration of barrier integrity. Keratinocytes express a high level of ␤2-adrenergic receptors (␤2-ARs) that appear to play a role in cutaneous homeostasis as aberrations in either keratinocyte ␤2-AR function or density are associated with various skin diseases. Here we report the novel finding that ␤-AR antagonists promote wound re-epithelialization in a "chronic" human skin wound-healing model. ␤-AR antagonists increase ERK phosphorylation, the rate of keratinocyte migration, electric field-directed migration, and ultimately accelerate human skin wound re-epithelialization. We demonstrate that keratinocytes express two key enzymes required for catecholamine (␤-AR agonist) synthesis, tyrosine hydroxylase and phenylethanolamine-N-methyl transferase, both localized within keratinocyte cytoplasmic vesicles. Finally, we confirm the synthesis of epinephrine by measuring the endogenously synthesized catecholamine in keratinocyte extracts. Previously, we have demonstrated that ␤-AR agonists delay wound re-epithelialization. Here we report that the mechanism for the ␤-AR antagonist-mediated augmentation of wound repair is due to ␤2-AR blockade, preventing the binding of endogenously synthesized epinephrine. Our work describes an endogenous ␤-AR mediator network in the skin that can temporally regulate skin wound repair. Further investigation of this network will improve our understanding of both the skin repair process and the multiple modes of action of one of the most frequently prescribed class of drugs, hopefully resulting in a new treatment for chronic wounds.

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Beta-adrenergic stimulation of cyclic AMP is defective in cultured dermal fibroblasts of psoriatic subjects

Cited by 17 publications

References 38 publications

The Effect of Cyclosporin A and FK 506 on the cAMP Content in Psoriatic Keratinocytes

The Effect of Cyclosporin A and FK 506 on the cAMP Content in Psoriatic Keratinocytes

The β2-adrenergic receptor activates pro-migratory and pro-proliferative pathways in dermal fibroblasts via divergent mechanisms

β-Adrenergic Receptor Antagonists Accelerate Skin Wound Healing

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