Tilts invention, was made with Government support under AR0S3542, awarded by the National Institutes of Health. The Government has certain rights in the invention. This work was supported by the U.S. Department of Veterans Affairs, and the Federal

Government has certain rights in the invention.

Priority Claim

This application claims the benefit: of priority to U.S. Provisional Patent Application

No. 61/979,389, filed on April 14, 2014, which is hereby incorporated by reference in its entirety.

Background

As the largest, organ, human skin provides the first line of defense against microbial pathogen-associated molecular patterns (PAMP) and physical and chemical damage- associated molecular patterns (DAMP). Ultraviolet (UV) irradiatioii has profound effects on hitman skin, causing sunburn, inflammation, cellular-tissue injury, photoaging and skin cancer. Most of these effects are mediated by proinflammatory cytokines produced by keratinocytes, such as l.L-6 and iL- .

Summary

Some aspects of the inventio relate to methods for treating, inhibiting, or

preventing various skin conditions in a patient, comprising administering interleukin-37, or a biologically active portion thereof, to the patient. Some embodiments of the invention relate to topical medicaments comprising a dermatologieally acceptable carrier or excipient and interleukin-37, or a biologically active portion thereof

Brief Description of the Figures

Figure 1 includes four panels, labeled panels (A), (B), (C), and (D). Panel (A) shows that IL-37 is induced in skin cells by P. acnes. Panel (B) shows that the immortalized human keraiiiiocvte ceil line HaCaT displays higher expression levels of IL-37 than monocytes in cytosol. Panel (C) shows that IL-37 is activated b F. acnes infection. Panei (D) shows that IL-37 is expressed at higher level in acnes lesions.

Figure 2 shows that exogenous IL-37 attenuates P. acnes-induced inflammation in the immortalized human keratinoeyte cell line HaCaT, and figure 2 includes three panels, labeled panels (A), (B), and (C). Panel (A) shows that P. acnes induced IL-6 expression in HaCaT in a dose dependent manner, Panei (B) shows that exogenous IL-37 reduces P. acnes- ^' mduecd IL-6 secretion in HaCaT. Panel (C) shows thai exogenous IL-37 reduced P. a jey-induced IL-8 secretion in HaCaT.

Figure 3 shows the anti-inflammatory effects of IL-37 on UVB-induced HaCaT cells, and figure 3 includes four panels, labeled panels (A), (B)„ fC), and (D). Panel (A) shows that UVB induces IL-6 secretion in HaCaT i a dose dependent manner. Panel (B) shows that UVB down-regulates IL-37 expression. Panel (C) shows that exogenous IL-37

compensated to reduce UVB-induced iL-6 secretion. Panel (D) shows that IL-37 ameliorates inflammation under the different doses of UVB.

Figure 4 shows that exogenous IL-37 attenuates . acnes- and UVB- induced IL-6 secretion by modulating NFKB p65 phosphorylation and ER signaling pathway, and figure 4 includes three panels, labeled panels (A), (B), and (C). Panel (A) shows that IL-37 reduces the phosphorylation of NFtcB p 5 and E K2. Panel (B) shows that IL-37 reduces the phosphorylation of NFKB p65 and ERK2 induced by P. acnes. Panel (C) shows that IL- 37 reduces the phosphorylation of NFKB p65 and ERK2 induced by UVB radiation.

Figure 5 shows that IL-18Rp and l ^' L-i8B ^' Pa are involved in exogenous IL-37 attenuated inflammation induced by UVB and P. acnes, and figure 5 includes three panels, labeled panels (A), (B), and (C). Panel (A) shows that IL-37 anti-inflammatory properties are dependent on IL-18Rf}. Panel (B) shows that IL-37 and l ^' L-18BPa additively inhibit IL-6 secretion induced by U B. Panel (C) shows that l ^' L-37 and IL-1 SBPa down-regulate IL-6 secretion induced by P. acnes.

Detailed Description

Overview

The balance of inflammatory and anti-inflammatory responses is critical to maintain immune homeostasis in skin. IL-37 is a potent: inhibitor of immunity by keeping the cytokine equilibrium from excessi ve inflammation, and it has shown broad inhibitory properties in the innate inflammatory and adaptive immune responses. IL-37 is a natural suppressor of innate inflammatory and immune responses. It serves as a dual-function cytokine with both intracellular and exiraceiiuiar mechanisms of action (Biila i A.M., et a!,, Proc. Natl Acad. Sci. U.S.A., 1 i 1(7):2650 (2034)).

IL-37 is absent in mice, but mice that express huma IL-37 are protected from lipopolysaccharide(LPS)-iiidu:ced shock, and showed markedly improved lung and kidney function and reduced liver damage after exposure to LPS ( okl M.F., et Nature Medicine, 1 1(1 1 ) : 1014 (2010)). Additionally, IL-37 plays a key role in intestinal inflammation because IL-37 expression protects mice from colitis (McNamee E.N., Proc. Natl Acad. Sci. U.S.A., 108(40): 1,671 1 (201 1».

In vivo expression of human iL-37 in mice reduces local and systemic inflammation in ConA-indueed hepatitis and LPS challenge (Bulau A.M., et at, Set. World. J., 1 1 :2480 (20.1 1 ); Sakai ., et a/. , J. Gastroenterol. Hepatol., 27(1): 1609 (201.2)). Additionally, IL-37 is involved in the pathophysiology of inflammatory bowel disease (IBD) as an antiinflammatory cytokine, and it is an inhibitor of both innate and acquired immune responses (!maeda H., et ah, Clin. Exp. Immunol., 172(3):4i0 (2013)). Further, IL-37 ameliorates the inflammatory process in psoriasis by suppressing pro-inflammatory cytokine expression (Teng ., J. Immunology, 192(4); 1815 (2014».

Although constantly assailed by stresses, the skin is not in a -perpetual state of inflammation. The processe underlying the skin's ability to keep inflammation subdued are not completely understood. IL-37, a member of the 11..- 1 famil of cytokines, has recently been shown to act as a potent inhibitor of inflammatory response. Skin tissue staining shows that IL-37 is present in high concentrations in epidermal keratinoeytes and in even higher quantities in chronic immune-mediated skin diseases, as psoriasis. As IL-37 is concentrated in the outer most layers of the skin, this cytokine may be important in the skin as a block to hyper reactive immunity. For example, the immortalized human keratmocyte cell line HaCaT does not actively secrete IL-37, but contains high cytosoiic concentrations of IL-37 (Figure l b). IL-37 is also an inducible cytokine as its gene expression increases at least 60% after treatment with P. acnes and UVB (p 0.05) and is upregulated in acne lesions (p<0.0 i ). The active spliced form of recombinant IL-37 inhibited UVB and P. acnes induction of T F-a, IL-Ιβ, and IL-6. This suggests that IL-37 has an anti-inflammatory role in response to damage- and pathogen-associated molecular patterns in keratinoeytes. Some aspects of the invention relate to the use of interleukin-37 (IL-37) as a treatment for inflammatory and autoimmune conditions, cancers, and wound healing. IL-37 was recently identified as a member of the IL-1 family of cytokines. Experiments in transgenic mice demonstrate that IL-37 has a role as a naturally occurring anti- inflammatory cytokine; however, IL-37 has not yet been studied extensively in the context of humans and human diseases.

The results provided herein show that IL-37 has a significant role in the regulation of inflammation and would healing as a result of both pathogenic and damage-rela ted stimuli, including i'lOpio h t nm acnes infection and ultraviolet B radiation. Through immuRohistochemisiry, IL-37 was found to be expressed at high concentrations in the epidermis, and it is both expressed and translated by keratinocytes. While this data suggests that active IL-37 is not actively secreted b keratinocytes in high concentrations, the active protein is present in relati vely high concentrations intraccllularly in

keratinocytes. This data suggests that active IL-37, therefore, participates m paracrine signally after apoptosis or cell damage.

The use of recombinant IL-37 in the presence of both *. acnes infection and UVB radiation are able to significantly reduce the induction of pro-inflammatory cytokines, including IL-6, and decrease the activation of nuclear factor kappa b (NFKB) and mitogen- aetivated protein kinases signaling. These latter signaling pathways have been shown to be tremendously important in the regulation of turaorigenesis and immune regulation.

Furthermore, IL-37 significantly nioduiates the expression of matrix metailoprofeinase 3 in a direction that correlates with improved clinical outcomes of scarring.

Therefore, appropriate levels of recombinant IL-37 can be administered for the prevention and treatment of infectious and damage-induced inflammatory skin diseases, autoimmune diseases, cancers, and to improve outcomes of scarring and wound healing.

Definitions

As used herein the specification, "a" or "an" may mean one or more. As used herein in the ciaim(s), when used in conjunction with the word "comprising" , the words "a" or "an" may mean one or more than one. As used herein "another" may mean at least a second or more.

The term "IL-ISBPa" refers to DL-18 binding protein isoform a. The term "prophylactic" or ' ^' therapeutic'" treatment is art-recognized and includes administration to the host- of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e. , it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

The term "preventing" is art-recognized, and when used in relation to a condition such as a local recurrence (e.g., blemish), a disease such as acne or psoriasis, or an injury such as sunburn, is wel! understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of acne includes, for example, reducing the number of detectable blemishes (i.e. , lesions) in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable blemishes in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount, Preven tion of psoriasis includes, for example, reducing the magnitude and/or frequency of lesions experienced by subjects in a treated population versus an untreated control population. Prevention of a sunburn includes, for example, reducing the severit of a sunburn.

The term "radiation burn" re ers to tissue burns (esp, skin burns) caused by thermal radiation, radio frequency energy, microwaves, ultraviolet light, x-rays, ionizing radiation, gamma radiation.

The term '"sunburn" refers to tissue bums (esp, skin burns) caused by exposure to ultraviolet radiation.

A "therapeutically effective amount" of a compound with respec t to the subject method of treatment refers to an amount of the compound! s) in a preparation which, when administered as part of a desired dosage regimen {to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, eg,, at a reasonable benefit/risk ratio applicable to any medical treatment. As used herein, the term "'treating" or "treatment ^* includes reversing, reducing, or arresting die symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject's condition. Exemplary Co tittjenis of Formulations

Exemplary identities of various constituents of the topical formulations of some embodiments of the present invention are described be!ow,

1 . Vehicles. Solvents, and Dil ents

Suitable topical vehicles and vehicle components for use with the formulations of the invention are well known in the cosmetic and pharmaceutical arts, and include such vehicles (or vehicle components) as water; organic solvents such as alcohols (particularly lower alcohols readily capable of evaporating from the skin such as ethanol), glycols (such as propylene glycol, butylenc glycol, and glycerol (glycerin)), aliphatic alcohols (such as lanolin); mixtures of water and organic solvents (such as wa ter and alcohol ), and mixtures of organic solvents such as alcohol and glycerol (optionally also with water); lipid-based materials such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphogSycerides, sphingoiipids and waxes; protein- based materials such as collagen and gelatin; si!icone-based materials (both non-volatile and volatile) such as cyclomediicone, dimediiconol, di ethieone. and dimethieone copolyol; hydrocarbon-based materials such a petrolatum and squalane; and other vehicles and vehicle components that arc suitable for administration to the skin, as well as mixtures of topical vehicle components as identified above or otherwise known to the art

In one embodiment, the compositions of the present invention are oil-in- water emulsions. Liquids suitable for use in formulating compositions of the present invention include water, and water-miscible solvents such as glycols (e.g. , ethylene glycol, butylene glycol, isoprene glycol, propylene glycol), glycerol, liquid po!yols, dimethyl sulfoxide, and isopropyl alcohol One or more aqueous vehicles may be present.

In one embodiment, formulations without methanol, ethanol, propanols, or butano!s are desirable.

.2, Surfactants and Emnlsifiers

Many topical formulations contain chemical emulsions which use surface active ingredients (emuistfiers and surfactants) to disperse dissimilar chemicals in a particular solvent system. For example, most lipid-like (oily or fatty) or lipophilic ingredients do not uniformly disperse in aqueous solvents unless they are first combined with eraulsifiers, which form microscopic aqueous soluble structures (droplets) that contain a lipophilic interior and a hydrophilic exterior, resulting in an oil-in-water emulsion. In order to be soluble in aqueous media, a molecule must be polar or charged so as to favorably interact with water molecules, which are also polar. Similarly, to dissolve an aqueous-soluble polar or charged ingredient in a largely lipid or oil-based solvent, an emulstfier is typically used which forms stable structures that contain the hydrophilic components in the interior of the structure while the exterior is lipophilic so that it can dissolve in the lipophilic solvent to form a water-io-oil emulsion. It is well known that such emulsions can be destabilized by the addition of salts or other charged ingredients which can interact with the polar or charged portions of the emulsifier within an emulsion droplet. Emulsion destabiiizatiort results in the aqueous and lipophilic ingredients separating into two layers, potentially destroying the commercial value of a topical product.

Surfactants suitable lor use in the present invention m y be ionic or non-ionic. These include, but are not limited to: ceryi alcohol, polysorbates (Polysorbate 20,

Polysorbate 40, Polysorbate 60, Polysorbate SO), steareth-10 (Brij 76), sodium dodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide, cety!trimethylamraooiura bromide (CTAB), polyethoxylated alcohols, polyoxyethylcne sorbitan, octoxynol, N,N- dimethyidodecylamine-N-oxide, feexadecyUrimethylammonium bromide (HTAB), polyoxyl 10 lauryl ether, bile salts (such as sodium deoxyeholate or sodium chelate), polyoxyl castor oil, nonylphenol ethox late, eyclodextrins, lecithin, dimethicone copolyol, lauramid© DEA, coeamide DBA, cocamide MEA, ofeyf betaine, cocamidopropyl betaine, cocamidopropyf phosphatidyl PG-dimonium chloride, dicetyi phosphate (dihexadecyi phosphate), ce.eare.h- 1 phosphate, methylbenzemonium chloride, dicetyi phosphate, ceteth-10 phosphate

( ^' ceteth-10 is the polyethylene glycol ether of cetyl alcohol where » has art average value of 10; ceteth- 10 phosphate is a mixture of phosphoric acid esters of ceteth-1 ), eeteth-20, Brij S10 (polyethylene glycol octadecyl ether, average M _n ~ 71 1), and Poioxamers (including, but not limited to, Poloxaracr 188 (HO(C ₂ H ₄ O CH(C¾)CH20 C2H40 ^' ) _a H ₅ average molecular weight 8400) and Poloxaracr 407 {HO(C2¾0) _a (CH(CH; _; CH ₂ 0 _b (C ₂ H ₄ 0) _a H, wherein a is about 101 and h is about 56)). Appropriate combinations or mixtures of such surfactants may also be used according to the present invention.

Many of t hese surfactants may also serve as emulsifiers in formulations of the present invention. Other suitable emu!stfiers for use in the formulations of the present invention include, but are not limited to, behentrimonium methositlfate-cetearyi alcohol, non-ionic emii!sifiers !ike emulsifying wax, polyoxyethylene oleyl ether, PEG-40 stearate, eetostearyl alcohol (cetearyl alcohol), ceteareth-12, ceteareth-20, eeteareth~30, ceteareth alcohol, Ceteth-20 (Ceteth-20 is the poly ethylene glycol ether of cetyl alcohol where n has an average value of 20), oleic acid, oie i alcohol, glyceryl stearate, PEG-75 stearate, PEG- 100 stearate, and PEG- 100 stearate, ceramide 2, ceramide 3, stearic acid, cholesterol, steareth-2, and steareth-20, or crmibinations/mixtures thereof, as well as cationie emulsifiers like stearamidopropyl diniethylamine and behentrimonium methosulfaie, or

combinations/mixtures thereof.

3. Moisturizers^ h- ^m ° f.i ' ^Cfs .<* H¾mectants

One of the most important aspects of topical products in general, and cosmetic products in particular, is the consumer's perception of the aesthetic qualities of a product For example, while white petrolatum is an excellent moisturizer and skin protectant, it is rarely used alone, especially on the face, because it is greasy, sticky, does not rub easily into the skin and ma soil clothing. Consumers highly value products which are aesthetically elegant and have an acceptable tactile feel and performance on their skin.

Suitable moisturizers for use in the formulations of the present invention include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerol, propylene glycol, butyiene glycol, sodium PCA, sodium hyaluronate, Carbowax 200, Carbo ax 400, and Carbowax 800,

Suitable emollients or humeetaiits for use in the formulations of the present invention include, but are not limited to, panthenol, cetyl palmitate, glycerol (glycerin), PPG-15 stearyl ether, lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyS neoperttartoate, oetyl stearate, mineral oik isocetyl stearate, myristyi myristate, oetyl dodecanoL 2-ethylhexyi palmitate (oetyl palmitate), dimethieone, phenyl

trimethicone, cyclomethicone, Ct2-C}$ alkyi henzoates, dimethiconol, propylene glycol, hmhrom gr ndifio m seed butter, ceramides (e.g., ceramide 2 or ceramide 3),

hydroxypropyl bispalmitamide MEA, hydroxypropyl bislauramide MEA, hydroxypropvl bisisostearamide MEA, .1 _! 3-bis(N-2~(hydroxyethyl)stearoylamino)-2 -hydroxy propane, bis* hydroxyethyi tocopherylsuccmoylaroido hydroxypropane, urea, aloe, allantoin,

giycyrrhetinic acid, safllower oil, olcyl alcohol, oleic acid, stearic acid. dicapryiate/dicaprate,, diethyl sehacate, isostearyl alcohol, pentylene glycol, isononyi isononanoate, and l,3-bls(N~2-(hydroxyethy1)palmuoylamino)-2-hydroxypropane.

In addition, appropriate combinations and mixtures of any of these moisturizing agents and emollients may be used in accordance with the present invention.

4. Preservatives and Antioxidants

The composition may further include components adapted to improve the stability or effectiveness of the applied formulation.

Suitable preservatives for use in the present invention include, but are not limited to: ureas, such as i idazolidinyi urea and diazotidioyl urea; phenoxyeihanoi; sodium methyl parahen, methy!paraben, ethylparaben, and propylparaben; potassium sorbate; sodium benzoate; sorbic acid; benzoic acid; formaldehyde; citric acid; sodium citrate; chlorine dioxide; quaternary ammonium compounds, such as benzalkomum chloride, benzethonium chloride, eetrimidc, deqimhn um chloride, and eetyipyridinium chloride; mercurial agents, such as phenylmereurie nitrate, phenylmereurie acetate, and thimerosal; piroctone olamine; Viiis vinifem seed oil; and alcoholic agents, for example, chlorobutanol, dichlorobenzyl alcohol phenylethyl alcohol, and benzyl alcohol

Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, butylatcd hydroxytoluene, buty!ated hydroxyamsole, tocopherols, tocophetyi acetate, sodium ascorbaie/ascorbic acid, ascorbyi palmitate, propyl galiate, and chelating agents like EDTA (e.g. , disodium EDTA), citric acid, and sodium citrate.

i certain embodiments, the antioxidant or preservative comprises (3-(4- chlorophenoxy)-2-hydroxypropyl carbamate.

In certain embodiments, antioxidants or preservatives of the present invention may also function as a moisturizer or emollient, for example.

in addition, combinations or mixtures of these preservatives or anti-oxidants may also be used in the formulations of the present invention.

5. Combination agents

The composition can also contain any other agent that has a desired effect when applied topically to a mammal, particularly a human. Suitable classes of active agents include, but are not limited to, antibiotic agents, antimicrobial agents, anti-acne agents, antibacterial agents, antifungal agents, antiviral agents, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, anesthetic agents, antipiitriginous agents, antiprotozoal agents, anti-oxidants, antihistamines, vitamins, and hormones. Mixtures of an of these active agents may also be employed Additionally, dermatoiogicaliy-acceptable sails and esters of any of these agents may be employed.

6. Buffer Salts

Suitable buffer sails are well-known in the art. Examples of suitable buffer salts include, but are not limited to sodium: citrate, citric acid, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate tribasic, potassium phosphate monobasic, potassium phosphate dibasic, and potassium phosphate tribasic.

7. Viscosity Modifiers

Suitable viscosity adjusting agents (i.e., thickening and thinning agents or viscosity modifying agents) for use in the formulations of the present invention include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethyleeiluiose, xanthan gum, and sclerotiura gum, as well as magnesium aluminum: silicate, silica, macrocrystalline wax, beeswax, paraffin, and cetyl palmitate. in addition, appropriate combinations or mixtures of these viscosity adjusters may be utilized according to the present invention.

Additional constituents suitable for incorporation into the emulsions of the present invention include, but are not limited to: skin protectants, adsorbents, demulcents, emollients, moisturizers, sustained release materials, solubilizing agents, skin-penetration agents, skin soothing agents, deodorant agents, antiperspirants sun screening agents, sunless tanning agents, vitamins, hair conditioning agents, anti-irritants, anti-aging agents, abrasives, absorbents, auti-caking agents, anti-static agents, astringents (e.g.. witch hazel, alcohol, and herbal extracts such as chamomile extract), bmders/excipiems, buffering agents, chelating agents, film forming agents, conditioning agents, opacifying agents, lipids, immunomodulators, and pH adjusters (e.g., citric acid, sodium hydroxide, and sodium phosphate).

For example, lipids normally found in healthy skin (or their functional equivalents) may be incorporated into the emulsions of the present invention, in certain embodiments, the Itpid is selected from the group consisting of ceramtdes, cholesterol, and free fatty acids. Examples of lipids include, but arc not limited to, eeramide 1, ceramide 2, eeramide 3, eeramide 4, eeramide 5, eeramide 6, hyd oxypropyl bispa.hnitam.ide MEA, and

hydroxy-propyl bislauramide MBA, and combinations thereof. Examples of peptides that interact with protein structures of the dermal-epidermal junction include paimitoyl dipeptide-5 diaminohutyloyl hydro y threonine and paimitoyl dipeptide-6 diaim ^' nohydroxybutyrate.

Examples of skin soothing agents include, but are not limited to algae extract, mugwort extract, stearyi glycyrrhetinate, bisabolol, allantoic aloe, avocado oik green tea extract, hops extract, chamomile extract, colloidal oatmeal, calamine, cucumber extract, and combinations thereof.

in certain embodiments, the compositions comprise bergamot or bergamot oil. Bergamot oil is a natural skin toner and detoxtiier. In certain embodiments, it may prevent premature aging of skin and may have excellent effects on oily skin conditions and acne.

Examples of vitamins include, but are not limited to, vitamins A, ΪΧ E, K, and combinations thereof. Vitamin analogues are also contemplated; for example, the vitamin D analogues eaieipotnene or caicipotriol.

i certain embodiments, the vitamin may be present as teirahexyldecyS ascorbate. This compound exhibits antioxidant activity, inhibiting lipid peroxidation, hi certain embodiments, use can mitigate the damaging effects ofUV exposure. Studies have shown it to stimulate collagen production as well as clarifying and brightening the skirt by inhibiting meianogenesis (the -production of pigment) thereby promoting a more even skin tone.

Examples of sunscreens include, but are not limited to, p-aramobmzoic acid, avobenzone, cinoxate, dioxybenzotie homosalate rnenthyl anthranilate, oetoerylene, octyl methoxycinnamate, octyl salicylate, oxybenzone, padimate O, phenylbenzimida ole sulfonic acid, sulisobenzone, titanium dioxide, trolamine salicylate, zinc oxide, 4- methyibenzylidene camphor, methylene bis-benzotriazolyi tetramethyibutylphenol, bis- eihyShexyloxyphenoi methox henyl triazine, terephthalyiideite dicamphor su!fonic acid, drometrizole trisiloxane, disodium phenyl dibenziroidazole tetrasuifbnate, diethviamino hydroxybenzoyl hexyl benzoaie, octyl triazone, diethylhexyl butamido triazone, polysilieone~15, and combinations thereof.

Suitable fragrances and colors ma be used in the formulations of the present invention. Examples of fragrances and colors suitable for use in topical products are known in the art.

Suitable inimunomodulators include, but are not limited to, tetrachlorodecaoxide, deoxycholic acid, tacrolimus, pimecraiimits, and bcta-glucan. In certain embodiments, paimitoyl-lysyl-valyMysioe bistrifiuoroacetate is added. This peptide stimulates collagen synthesis in human fibroblasts.

Often, one constituent of a composition may accomplish several functions. In one embodiment, the present invention relates to constituents that may act as a lubricant, an emollient, or a skin-penetrating agent. In one embodiment, the multi-functional constituent is socet l stearate, isopropyi isostearate, isopropyi palmitate, or isopropyi myristate.

.Exemplary Uses

Normal skin cells express low levels o IL-37. As shown herein, IL-37 is a potent inhibitor of immunity by keeping the cytokine equilibrium from excessi ve inflammation, and it showed broad inhibitory properties in the innate inflammatory and adaptive immune responses. One of ordinary skill in the art will appreciate that various inflammatory conditions can be treated, prevented, or their onset delayed by administering IL-37. in particular, the invention relates to the treatment of inflammatory skin conditions, including acne, actinic keratosis, chemical burn, contact dermatitis, bacterial infection, dermatitis, electrical bums, eczema, folliculitis, fungal infection, hives, photoaging, pityriasis rosea, poison ivy, psoriasis, pyoderma gangrenosum, radiation bum, rosacea, seborrhoeic eczema, sunburn, thermal bum, viral infection, and yeast infection. Additionally, ultraviolet CUV) irradiation has profound effects on human skin, causing sunburn, inflammation, cellular- tissue injury, photoaging and skin cancer. Most of these effects are mediated b proinflammatory cytokines produced by keratinocytes, such as 1L-6 and lL-8, Exogenous 1L- 37 can reduce the production of 1L-6 and 1L-8 by keratinocytes, and thus, exogenous IL-37 can be administered to treat, prevent, or delay the onset of skin condition caused by UV radiation. Specifically, exogenous 1L-3? attenuates cytokine secretion by modulating NF B phosphorylation and ER signaling (Figure 4),

Exogenous IL-37 reduces Propiomhact rium aems-mdn td IL-6 and 1L-8 secretion in keratinocytes (figure 2). Therefore, in some aspects, the invention relates to methods of treating, inhibiting, or preventing bacterial infections caused by Ptoptonih cierUtm by administering an effective amount of iti.terleukin-37, or a biologically active portion thereof in other aspects, the invention relates to methods of treating, inhibiting, or preventing bacterial infections caused by P. acnes by administering an effective amoun t of iiiterieukin- 37, or a biologically acti ve portion thereo P. acnes causes acne. Thus, the invention provides methods of treating, inhibiting, or preventing acne by administering an effective amount of interteukin-37, or a biologically active portion thereof.

As practitioners with ordinary skill in the art will recognize, treatment of P. acnes correlates with the treatment of other bac terial infections of the skin.. Therefore, in some aspects, the invention relates to methods of treating, inhibiting, or preventing bacterial infections by administering an effective amount of interleukm-37, or a biologically active portion thereof.

Ultraviolet B radiation reduces the expression of IL-37 in keratinocytes. Exogenous IL-37, however, compensates for UVB-induced IL-37 downregulation and reduces UVB- indueed lL-6 secretion (Figure 3). Thus, in some aspects, the invention relates to methods of treating, inhibiting, or preventing UV-hiduced skin damage, by administering an effective amount of intcrlcukin-37, or a biologically active portion thereof,

IL-37 is highly expressed in psoriasis lesions. cratinoeytes, however, do not actively secrete IL-37. Therefore, in some aspects, the invention relates to methods of treating, inhibiting, or preventing psoriasis, by administering an effective amount of interieukm-37, or a biologically acti ve portion thereof.

IL-37 and IL~ I 8BPa additive!y inhibit IL-6 secretion by keratmoevtes. Therefore, in some aspects, the invention relates to methods of treating skin conditions by

administering an effective amount of IL-37 and IL18Bpa.

In some embodiments, the invention relates to a method of inhibiting or preventing fibrosis (such as formation of scar tissue) in a patient, comprising administering interieukin- 37 or a biologically acti ve portion thereof to the patient.

in some embodiments, the in vention relates to a method of treating a wound in a patient, comprising administering tnterieukin-37 or a biological ly active portion thereof to the patient.

^' The administration of IL-37 may be topical, transdermal, oral, sublingual _; , intradermal, subcutaneous, intravenous, intramuscular, intraperitoneal, or inhalation. In preferred embodiments, administration is topical, transdermal, oral, intradermal, or subcutaneous, in more preferred embodiments, administration is topical. A topical composition comprising IL-37 (or a biologically acti ve portion thereof) may comprise, for example, a dermatologicaily acceptable carrier or exe pient and mterleukin-37 (or a biologically active portion thereof), in some embodiments, the method comprises administering an effective amount- of i.L- 1 8B.PA, or a biologically active portion thereof. n some embodiments, administering comprises applying IL-37 (such as a compositioii comprising IL-37) to an area of skin.

In some embodiments, the invention relates to a topical medicament,, comprising a derraatologicaliy acceptable carrier or excipient and inierleukin-37, or a biologically active portion thereof. The topical medicament may further comprise IL-18.BPa, or a biologically active portion thereof.

Incorporation by Reference

All patents, published patent applications, and other publication mentioned irt the description above are incorporated by reference herein in their entirety.

Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.