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1 ORIGINAL ARTICLE JEADV (21) 15 (Suppl. 3), Exploration of retinoid activity and the role of inflammation in acne: Blackwell Science Ltd issues affecting future directions for acne therapy CC Zouboulis Department of Dermatology, University Medical Center Benjamin Franklin, The Free University of Berlin, Fabeckstrasse 6 62, Berlin, Germany. tel ; fax ; zouboulis@medizin.fu-berlin.de ABSTRACT The review summarizes new results concerned with several important issues in the treatment of patients with acne. The first section reviews studies which show that 13-cis retinoic acid, a molecule with strong biological activity but low binding affinity for retinoid receptors and cellular-binding proteins in sebocytes, undergoes rapid intracellular conversion to all-trans retinoic acid. This active metabolite exerts its actions on sebocyte gene expression by binding to the nuclear retinoic acid receptor rather than the retinoid X receptor. Importantly, 13-cis retinoic acid, unlike all-trans retinoic acid, does not induce cytochrome P45 1A1, an enzyme responsible for the metabolism of xenobiotics. Thus, administration of 13-cis retinoic acid permits high long-term intracellular accumulation of its active metabolite. The second section reviews studies which suggest that leukotriene B4 may play a key role in acne-related inflammation. Results from a preliminary clinical study indicate that therapy with a specific lipoxygenase inhibitor is clinically effective in the treatment of patients with inflammatory acne and that its clinical efficacy is correlated with the drug s ability to reduce total lipid levels, and especially pro-inflammatory lipids, in sebum. Interestingly, 13-cis retinoic acid has been shown to modulate the activities of LTB4 and inflammatory events in the development of acne. Therefore, future compounds targeting acne have to inhibit pro-inflammatory lipids in sebum, and thus down-regulate acne-related inflammatory signals and reduce the LTB4-induced migration of inflammatory cells. Key words: 13-cis retinoic acid, all-trans retinoic acid, acne, inflammation interleukin-1, leukotriene B4, lipids Introduction Research on acne treatment has expanded markedly in the last several years. The results of numerous studies have greatly increased our understanding of both the pathophysiology of the disease and the mechanisms of action for current therapies. This review focuses on two distinct issues. The first section of the paper is concerned with the intracellular metabolism of 13-cis retinoic acid in sebocytes and the nuclear receptors that mediate the action of its active metabolite in the treatment of acne. The second part of the review focuses on the role of pro-inflammatory molecules in acne development. It also summarizes results from a preliminary, small-scale clinical study that has evaluated the effects of a new anti-inflammatory agent that specifically blocks the formation of leukotriene B4 (LTB4) in patients with acne. 13-cis Retinoic acid: selective action in sebocytes 13-cis retinoic acid has been shown to significantly inhibit sebocyte proliferation, differentiation, and lipid synthesis in vivo and in vitro. 1,2 However, the molecular basis for the unique antisebotropic action of this compound is not fully understood. 3,4 The high antisebotropic activity of 13-cis retinoic acid is particularly surprising because it has low binding affinities for both cellular retinoic acid-binding proteins I and II as well as for nuclear retinoid receptors [retinoic acid receptors (RAR) and retinoid X receptors (RXR)]. 5,6 Retinoids are thought to exert most of their effects by modulating gene expression and/or activating nuclear retinoid receptors and it has been suggested that 13-cis retinoic acid may act as a prodrug that becomes active after isomerization to all-trans retinoic acid or conversion to 9-cis retinoic acid. 6 Until recently, there has been very little direct evidence to support these suggestions. Conversion of 13-cis retinoic acid to all-trans retinoic acid Results reported by Tsukada et al. have shown that 13-cis retinoic acid does indeed undergo significant isomerization to all-trans retinoic acid in cultured sebocytes. 7 When 13-cis 21 European Academy of Dermatology and Venereology 63
2 64 Zouboulis cRA atra Concentration (nm) time (h) fig. 1 Metabolism of 13-cis retinoic acid (13cRA) after administration to cultured sebocytes. 7 P <.1, P <.1, P <.1 vs. all-trans-retinoic acid (atra). retinoic acid is administered to these cells, there is a slight rise in the intracellular concentration of this molecule followed by a fairly rapid decline (fig. 1). In contrast, there is a marked increase in the intracellular levels of all-trans retinoic acid that decline much more slowly. These results strongly support the conclusion that 13-cis retinoic acid undergoes isomerization to all-trans retinoic acid in sebocytes. Importantly, this isomerization is specific to sebocytes. Administration of 13-cis retinoic acid to keratinocytes did not result in a substantial rise in the intracellular concentration of all-trans retinoic acid. 7 The high accumulation of all-trans retinoic acid in sebocytes after administration of 13-cis retinoic acid appears not only to involve isomerization of this molecule to all-trans retinoic acid but also to reduce activation of the cytochrome P45 (CYP45) 1A1 which is involved in the metabolism of xenobiotics. All-trans retinoic acid is metabolized primarily by CYP45 isoenzymes (e.g. 1A1, 26) that are rapidly up-regulated when all-trans retinoic acid is delivered to epithelial cells. In contrast, administration of 13-cis retinoic acid to sebocytes and its subsequent intracellular conversion to all-trans retinoic acid results in significantly less induction of CYP45 1A1 and thus higher intracellular levels of all-trans retinoic acid. 7 Thus, administration of the inactive pro-drug, 13-cis retinoic acid, permits the development of high intracellular levels of its active metabolite, all-trans retinoic acid, without the induction of the CYP45 isoenzymes responsible for its inactivation. Receptors involved in the activity of 13-cis retinoic acid The experiments reported have also elucidated the nuclear receptors involved in the activity of 13-cis retinoic acid. As noted above, administration of 13-cis retinoic acid inhibits the proliferation of sebocytes. Administration of all-trans retinoic acid produces a similar antiproliferative effect. 3,7,8 However, when a selective RAR antagonist (AGN 19319) was administered along with 13-cis retinoic acid a complete abolition of the antiproliferative effect of this retinoid was detected (fig. 2). This effect was independent of any action on AGN on the metabolism of 13-cis retinoic acid. Co-administration of AGN also antagonized the antiproliferative effect of alltrans retinoic acid, but at a tenfold higher concentration than required for 13-cis retinoic acid (fig. 2). 7 Similar experiments were also carried out with a selective RXR antagonist, CD 357. Co-administration of this drug with 13-cis retinoic acid or all-trans retinoic acid had no effect on the antiproliferative activity of either retinoid. 7 Thus, all these results support the overall conclusion that 13-cis retinoic acid is selectively and rapidly converted to all-trans retinoic acid in sebocytes which then acts via RAR to exert its antiproliferative effect on these cells. The role of inflammation in acne The four factors suggested to be necessary for the development of acne are well defined and they include: seborrhoea; obstruction of the hair follicle and the ductus seboglandularis by follicular hyperkeratosis; hypercolonization of the follicular canal with bacteria; and inflammation of the follicle. 9,1 The remainder of this paper focuses on the last of these factors, the follicular inflammation. Expression of pro-inflammatory cytokines in the sebaceous gland It is widely accepted that inflammation in acne vulgaris may be mainly induced by an immunological reaction to extracellular
3 Retinoid activity and the role of inflammation fig. 2 Effects of 13-cis retinoic acid (13cRA), alltrans retinoic acid (atra), and 9-cis retinoic acid (9cRA) on sebocyte proliferation alone and in the presence of AGN 19319, a specific RAR antagonist. 7 Results are % of control. First point in each panel shows effect of retinoid alone. P <.5, P <.1 vs. control. Cell proliferation (%) cRA (1 7 M) atra (1 7 M) 9cRA (1 7 M) AGN AGN AGN AGN log [AGN 19319] products of Propionibacterium acnes. 11 However, it is by no means clear that either bacteria or their products initiate follicular inflammation. Ingham et al. investigated the presence of pro-inflammatory cytokines in 18 open acne comedones from 18 untreated acne patients. 12 Bioactive interleukin (IL)-1 alpha-like material was demonstrated in 76% of open comedones; in 58%, levels exceeded 1 pg/mg. The majority of open comedones (97%) also contained micro-organisms, but there was no significant correlation between levels of any cytokine, in particular IL-1 alpha, and numbers of micro-organisms. Additional results have shown that the sebaceous gland expresses a number of different cytokines at steady state, without the influence of any external factors. Antilla et al. showed that IL-1 is present in normal sebaceous glands 13 and Boehm et al. used in situ hybridization techniques to show that messenger RNA (mrna) for IL-1 alpha, IL-1 beta, and tumour necrosis factor (TNF)-alpha are present at multiple sites in normal skin, including the sebaceous glands. 14 Thus, while the presence of bacteria, most notably P. acnes, 15 may up-regulate cytokine expression in sebaceous glands, pro-inflammatory cytokines are expressed in these tissues in the absence of defined external influences. Action of pro-inflammatory cytokines in acne development Guy et al. assessed the action of IL-1 in the human pilosebaceous infundibulum isolated by microdissection and maintained in keratinocyte serum-free culture for 7 days. 16 The addition of 1 ng/ml IL-1 alpha resulted in hypercornification of the infundibulum similar to that seen in comedones. The dependence of this effect on a specific action of IL-1 alpha was confirmed in an additional experiment that showed that the IL-1 alpha effect could be annulled by 1 ng/ml IL-1 receptor antagonist. Additional results demonstrated further that spontaneous hypercornification of the infundibulum (which occurred in about 2% of isolated pilosebaceous units) could also be blocked by the IL-1 alpha receptor antagonist. These results provide logical support for the use of anti-inflammatory regimens in the treatment of acne. Leukotriene B4 The use of anti-inflammatory drugs for the treatment of acne is further supported by recent results indicating a key role for leukotriene B4 (LTB4) in the development of tissue inflammation. 17 LTB4 is a pro-inflammatory mediator synthesized from arachidonic acid. Synthesis of LTB4 is catalysed by 5- lipoxygenase and leukotriene A4 hydrolase and is increased by inflammatory mediators including endotoxin, complement fragments, TNF-alpha and interleukins. LTB4 induces recruitment and activation of neutrophils, monocytes and eosinophils. It also stimulates the production of a number of pro-inflammatory cytokines and mediators that augment and prolong tissue inflammation. Limited data from pharmacological inhibition studies support a role for LTB4 in the pathogenesis of neutrophilmediated tissue damage. 17 Due to its potential importance in the inflammatory events involved in acne, we evaluated the role of a specific lipoxygenase inhibitor on acne in a small cohort of patients. 18 We carried out a 3-month study of the effectiveness of this drug in 1 patients with inflammatory acne. Clinical evaluation of these patients indicated an approximately 6% decrease in the acne severity index within 3 weeks of the initiation of treatment (fig. 3) and a 7% reduction in inflammatory lesions at 3 months. There was no effect of treatment on plasma levels of LTB4. Additional evaluation of laboratory results from these patients indicated an approximately 65% reduction in total lipids in sebum as well as a substantial decrease in lipoperoxides. Free fatty acids were also decreased by almost 8%. Bivariate analysis indicated that the decrease in total serum lipids, and especially in proinflammatory lipids, was directly correlated with the improvement
4 66 Zouboulis 6 5 Disease severity index Weeks 41 ± 28% fig. 3 Effects of treatment with a specific lipoxygenase inhibitor on acne severity over 12 weeks of treatment and 2 weeks after discontinuation of treatment. 18 P <.5, P <.1, n = 1. in inflammatory lesions. Thus, the results of this small-scale clinical trial and associated laboratory analysis strongly support the conclusion that acne is likely to be an inflammatory disease 19 and that appropriate anti-inflammatory therapy has the potential to effectively treat this condition. These results also support the view that sebum lipids induce inflammation in acne, independent of the presence of bacteria or increased systemic levels of pro-inflammatory molecules 19. The results of a final study provide a bridge between the findings summarized in the first section of this paper and those set forth immediately above. Ten years ago, Wozel et al. assessed the ability of 13-cis retinoic acid as well as a number of other agents to inhibit transdermal migration of polymorphonuclear leucocytes (PMNs) stimulated by LTB4. 2 Topical treatment with 13-cis retinoic acid resulted in a marked and statistically significant inhibition of the LTB4-induced migration of PMNs. All-trans retinoic acid, arotinoid methyl sulphone, and arotinoid ethyl sulphone also reduced the accumulation of PMNs, but these effects were not statistically significant. Thus, 13-cis retinoic acid has also the potential to modulate the activities of LTB4 and inflammatory events in the development of acne. Summary This brief review summarized new results concerned with two important issues in the treatment of patients with acne. The studies described in the first part demonstrate that 13-cis retinoic acid, an agent highly effective for the treatment of acne but with little intrinsic activity in sebocytes, undergoes rapid intracellular conversion to all-trans retinoic acid. This active metabolite exerts its action on sebocyte gene expression by binding to RARs. An important feature of delivery of 13-cis retinoic acid rather than all-trans retinoic acid to sebocytes is that the former retinoid does not induce CYP45 isoenzymes while the latter molecule does. Thus, administration of 13-cis retinoic acid permits greater intracellular accumulation of the active molecule. The studies reviewed in the second part support the wellestablished view that inflammatory processes play a key role in the development of acne. However, they also indicate that bacterial infection is not necessary for expression of pro-inflammatory cytokines. Preclinical studies also suggest that LTB4 may play a key role in acne-related inflammation. Results of a preliminary clinical study indicate that therapy with a specific lipoxygenase inhibitor is effective in the treatment of patients with inflammatory acne and that its clinical efficacy is correlated with the drug s ability to reduce lipid levels in sebum. In conclusion, future compounds targeting acne have to be able to reduce pro-inflammatory lipids in sebum, down-regulate proinflammatory signals in the pilosebaceous unit and inhibit LTB4-induced accumulation of inflammatory cells. References 1 Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC. Current use and future potential role of retinoids in dermatology. Drugs 1997; 53:
5 Retinoid activity and the role of inflammation 67 2 Zouboulis CC, Orfanos CE. Retinoids. In: Millikan, LE, ed. Drug Therapy in Dermatology. Marcel Dekker, New York Basel, 2: Zouboulis CC, Korge B, Akamatsu H, et al. Effects of 13-cis-retinoic acid, all-trans-retinoic acid and acitretin on the proliferation, lipid synthesis and keratinexpression of cultured human sebocytes in vitro. J Invest Dermatol 1991; 96: Zouboulis CC, Korge BP, Mischke D, Orfanos CE. Altered proliferation, synthetic activity, and differentiation of cultured human sebocytes in the absence of vitamin A and their modulation by synthetic retinoids. J Invest Dermatol 1993; 11: Allenby G, Bocquel MT, Saunders M, et al. Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids. Proc Natl Acad Sci USA 1993; 9: Sitzmann JH, Bauer FW, Cunliffe WJ, Holland DB, Lemotte PK. In situ 13-cis hybridization analysis of CRABP II expression in sebaceous follicles from retinoicacid-treated acne patients. Br J Dermatol 1995; 133: Tsukada M, Schröder M, Roos TC, et al. 13-cis Retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors. J Invest Dermatol 2; 115: Zouboulis CC, Seltmann H, Neitzel H, Orfanos CE. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95). J Invest Dermatol 1999; 113: Brown SK, Shalita AR. Acne vulgaris. Lancet 1998; 351: Zouboulis CC. Acne: Current aspects on pathology and treatment. Dermatol Experiences 1999; 1: Burkhart CG, Cantrill J, Butcher CL, Lehmann PF. Propionibacterium acnes. Interaction with complement and development of an enzyme-linked immunoassay for the detection of antibody. Int J Dermatol 1999; 38: Ingham E, Eady EA, Goodwin CE, Cove JH, Cunliffe WJ. Pro-inflammatory levels of interleukin-1 alpha-like bioactivity are present in the majority of open comedones in acne vulgaris. J Invest Dermatol 1992; 98: Antilla HS, Reitamo S, Saurat JH. Interleukin 1 immunoreactivity in sebaceous glands. Br J Dermatol 1992; 127: Boehm KD, Yun JK, Strohl KP, Elmets CA. Messenger RNAs for the multifunctional cytokines interleukin-1 alpha, interleukin-1 beta and tumor necrosis factor-alpha are present in adnexal tissues and in dermis of normal human skin. Exp Dermatol 1995; 4: Vowels BR, Yang S, Leyden JJ. Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: Implications for chronic inflammation in acne. Infect Immun 1995; 63: Guy R, Green MR, Kealey T. Modeling acne in vitro. J Invest Dermatol 1996; 16: Crooks SW, Stockley RA. Leukotriene B4. Int J Biochem Cell Biol 1998; 3: Zouboulis CC, Nestons S, Adler YO, et al. An oral 5-lipoxygenase inhibitor reduces inflammatory lesions and total pro-inflammatory sebum lipids in acne vulgaris. J Invest Dermatol 21; 117: Zouboulis CC. Is acne vulgoris a genuine inflammatory disease? Dermatology, in press. 2 Wozel G, Chang A, Zultak M, et al. The effect of topical retinoids on the leukotriene-b4-induced migration of polymorphonuclear leukocytes into human skin. Arch Dermatol Res 1991; 283:
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