<i>cis</i>-Urocanic Acid Induces Mast Cell Degranulation and Release of Preformed TNF--α: A Possible Mechanism Linking UVB and <i>cis</i>-Urocanic Acid to Immunosuppression of Contact Hypersensitivity

Abstract

The search for effective inhibitors of transdermal drug-induced contact sensitization was directed to dermal mast-cell-degranulating agents (MCDA). Human skin organ cultures were employed to test whether cis-urocanic acid (C-UA) and other potential MCDAs cause mast cell degranulation. These were then tested for their ability to inhibit the induction phase of the contact hypersensitivity reaction (CHR). C-UA at 1 μg/ml significantly depleted mast cell chymase, whereas trans-urocanic acid (T-UA) was relatively ineffective. C-UA, but not T-UA, induced local effects of liberated mast cell TNF-α, as detected by E-selectin expression on the microvascular dermal endothelium. C-UA significantly reduced (>70%) the ear swelling response in Balb/c mice, when applied 24 h prior to application of a sensitizing amount of dinitrochlorobenzene (DNCB), and induced a prolonged (>3 weeks) state of immune tolerance (>40%). Similar effects on local immunosuppression of CHR were observed with topical chloroquine and capsaicin, while cromolyn, a mast cell membrane stabilizer, was unable to inhibit DNCB-induced CHR. It is suggested that MCDAs may interfere with downstream events associated with accessory cell function.

Three Randomised Phase I/IIa Trials of 5% Cis-urocanic Acid Emulsion Cream in Healthy Adult Subjects and in Patients with Atopic Dermatitis

“…In all assessments, the 5% cis-UCA emulsion cream was found well tolerated both locally on the skin and systemically. Several previous studies in a total of 80 adult subjects exposed to single or repeated doses of topical cis-UCA formulations (9,(14)(15)(16)(17)(18) also on large skin areas (9) confirm our tolerability findings. In each of these studies, the positive anti-inflammatory response to cis-UCA treatment could be verified and no adverse effects or treatment-related local or systemic side effects were reported.…”

Increased epidermal filaggrin in chronic idiopathic urticaria is associated with severity of urticaria

“…As PGE2 has been shown to induce an EP3 receptor-dependent mast cell degranulation and to increase microvascular permeability and infiltration of inflammatory cells into tissues, an increase of PGE2 may contribute to wheal reaction. It has also been reported that cis -UCA stimulates mast cell degranulation directly as well as indirectly by inducing neuropeptide release from peripheral sensory nerves in skin (21). On the other hand, histidine, the major component amino acid of filaggrin, is a substrate of mast cell histidine decarboxylase (HDC) producing histamine.…”

Mast cells and cutaneous malignancies

“…Cis-UCA stimulates neuropeptide secretion, especially substance P and calcitonin gene-related peptide, from cutaneous sensory nerves. 47,51,52 These neuropeptides in turn stimulate release of mediators from mast cells. Secondly, irradiated keratinocytes secrete nerve growth factor, which sustains release of neuropeptides from the sensory nerves.…”