Naturalne inhibitory cytokin w leczeniu Łuszczycowego zapalenia stawów ŁZS

Łuszczycowe zapalenie stawów jest przewlekłą chorobą zapalną stawów oraz skóry   ŁZS  w której pośredniczy układ immunologiczny oraz mikroflora jelitowa. Progresja choroby jest związana z nieprawidłową ekspresją cytokin prozapalnych . Hamowanie ekspresji cytokiny czynnika martwicy guza TNF-alfa(ang. Tumor Necrosis Factor) było do niedawna jedną z najbardziej skutecznych terapii tej choroby . Jednak nie  wszyscy pacjenci reagują pozytywnie na leczenie syntetycznymi inhibitorami TNF takim jak infliximab, adalimumab czy etanercept. Dziś już wiemy że nie tylko cytokina TNF-alfa ale również interleukiny prozapalne IL-23 oraz IL-17 uczestniczą w nasileniu objawów ŁZS [1],[3]. Lek o nazwie secukinunab jest przeciwciałem monoklonalnym IgG1 które selektywnie wiąże i neutralizuje interleukine IL-17A, której skuteczność w leczeniu przewlekłej łuszczycy wykazano w różnych badaniach klinicznych fazy II [4].Kolejną cytokiną biorącą udział w  ŁZS jest Interleukina IL-36α która uruchamia prozapalne interleukiny IL-6 oraz IL-8 indukujące zapalenie błony maziowej stawów  [2]. Główny nacisk na leczenie ŁZS to wygaszenie  cytokin pozapalnych odpowiedzialnych za ta chorobę .

Mikrobiom (mikroflora jelitowa) jest aktualnie przedmiotem rosnącego zainteresowania etiologii chorób zapalnych o podłożu immunologicznym. Mikroflora jelit jest w stanie wpływać na bardzo odległe miejsca w organizmie człowieka takie jak np stawy oraz skóra poprzez sterowanie naszym układem immunologicznym. Mamy coraz więcej dowodów dotyczących związku między mikrobiomem , układem immunologicznym a łuszczycowym zapaleniem stawów. Bakterie probiotyczne  Bifidobacterium infantis wyciszają cytokiny prozapalne w przebiegu ŁZS.

Leki pochodzenia naturalnego takie jak (zioła ,probiotyki, grzyby ) mogą być skuteczną alternatywą dla syntetyków. Ich zalety to niewątpliwie mniej skutków ubocznych ,łatwa dostępność oraz niska cena w porównaniu z najnowszymi terapiami oferowanymi nam przez koncerny farmaceutyczne.

Roślinne inhibitory cytokin w leczeniu ŁZS:

1) Rośliny hamujące TNF-alfa:

Uczep (Bidens bipinnata , Bidens pilosa) – W tradycyjnej medycynie chińskiej i indyjskiej jest stosowany w leczeniu zapaleniu stawów i łuszczycy. Silnie hamuje cytokiny TNF-alfa ,IL-8 [8] . Ekstrakt z nadziemnych częsci na etanolu 40% 1:3 . Dawkowanie 5ml trzy razy dziennie.

Biodiversity, Plant Inventory Mbizi Forest Reserve and Rukwa Reg

2) Rośliny hamujące interleukiny IL-17 oraz IL-23:

Ku shen (Sophorae flavescentis) – W tradycyjnej medycynie chińskiej (TCM) Ku shen stosowano w formule Xiao Feng Wan w leczeniu swędzenia skóry, czerwonych zmian na skórze, łuszczycy, wyprysków, trądziku, stanów zapalnych skóry. Hamuje interleukiny IL-23 oraz IL-17 [6]. Ekstrakt z korzenia na etanolu 70% 1:3. Dawkowanie 5 ml trzy  razy dziennie  co 8 godzin. Korzeń Ku shen jest dostępny na http://www.ebay.pl oraz http://www.allegro.pl

Ku shen

3) Rośliny hamujące interleukiny Il-6,IL-8 aktywowane przez IL-36 alfa:

Butea monosperma – W tradycyjnej medycynie indyjskiej (Ayurveda) jest stosowana w leczeniu łuszczycy. Hamuje interleukiny Il-1,Il-6,IL-8 [7] . Ekstrakt z kwiatów na etanolu 40%-50% 1:5.Dawkowanie 5 ml trzy razy dziennie co 8 godzin. Można stosować jako wartościowy zamiennik susz z kwiatów Butea superba który można kupić na ww.ebay.pl.

Bueta

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Bibliografia

[1]  
Autoimmun Rev. 2014 Jan 11. pii: S1568-9972(14)00062-7. doi: 10.1016/j.autrev.2014.01.050. [Epub ahead of print]The IL-23/IL-17 axis in psoriatic arthritis.Suzuki E1, Mellins ED2, Gershwin ME1, Nestle FO3, Adamopoulos IE4.
Abstract

Psoriatic arthritis (PsA) is an immune-mediated chronic inflammatory disease, affecting both the skin and joints. Disease progression is associated with aberrant cytokine expression, and TNF blockade is the most successful therapy to date. However, not all patients are responsive to anti- TNF treatment, highlighting the need to better understand the cellular and molecular mechanisms

that govern the disease. PsA associations with single nucleotide polymorphisms in IL23R as well as TRAF3IP2 (Act1), a molecule downstream of the IL-17 receptor (IL-17R), have linked the IL-23/IL-17 axis to disease pathology. Although both cytokines are implicated in PsA, a full picture of their cellular targets and pathogenic mechanisms has not yet emerged. In this review, we focus on the
IL-23/IL-17 axis-elicited responses mediated by osteoclasts, keratinocytes and neutrophils. Expanding our understanding of the cellular and molecular mechanisms that dictate pathogenicity in PsA will contribute to developing novel treatment strategies to combat disease.


[2]
Ann Rheum Dis. 2013 Sep 1;72(9):1569-74. doi: 10.1136/annrheumdis-2012-202264. Epub 2012 Dec 25.The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium.Frey S, Derer A, Messbacher ME, Baeten DL, Bugatti S, Montecucco C, Schett G, Hueber AJ.
Author information

Abstract
BACKGROUND:

Interleukin (IL)-36α is a recently described member of the IL-1 cytokine family with pro- inflammatory and clearly pathogenic properties in psoriasis.

OBJECTIVE:
To determine the IL-36α expression in psoriatic arthritis (PsA) compared to rheumatoid arthritis
(RA) and osteoarthritis (OA).

METHODS:
Synovial tissues obtained from arthritis patients were stained for IL-36α, IL-36 receptor (IL-36R) and IL-36R antagonist (IL-36Ra) by immunohistochemistry and immunofluorescence. Lysates were examined for IL-36α by western blot analysis. Synovial fibroblasts (FLS) cultured in the presence of IL-36α were assayed for cytokine expression by quantitative real time PCR and multiplex assay.
IL-36α-induced signal transduction in FLS was analysed by immunoblotting.
RESULTS:
Expression of IL-36R and its ligands IL-36α and IL-36Ra was detected in the synovial lining layer and cellular infiltrates of patients with inflammatory arthritis. IL-36α was expressed significantly higher in PsA and RA than in OA synovium. CD138-positive plasma cells were identified as the main cellular source of IL-36α. No differences were observed for the expression of IL-36R and IL-36Ra between PsA, RA and OA. Functionally, IL-36α induced the expression of IL-6 and IL-8 in FLS through p38/NFkB activation.

CONCLUSIONS:
IL-36α is up-regulated in PsA and RA synovium, expressed by tissue plasma cells and leads to IL-6 and IL-8 production by synovial fibroblasts. Hence, IL-36α links plasma cells to inflammatory cytokine production by FLS and may represent a key link between autoimmunity and the induction of synovitis.


[3]
Clin Rev Allergy Immunol. 2013 Apr;44(2):183-93. doi: 10.1007/s12016-012-8307-1.
Role of IL-17 in psoriasis and psoriatic arthritis.
Raychaudhuri SP.

Author information
Abstract

The role of T cell subpopulations in human disease is in a transition phase due to continuous discovery of new subsets of T cell, one of which is Th17, characterized by the production of signature cytokine IL-17. In the last couple of years, many articles are coming out on the role of Th17 and its signature cytokine IL-17 in different autoimmune diseases like rheumatoid arthritis, psoriasis, psoriatic arthritis (PsA), SLE and multiple sclerosis. Psoriasis and PsA are immune- mediated diseases, affecting the skin and joints, respectively. Initially, it was thought that psoriasis and PsA were Th1-mediated diseases; however, studies in knockout animal models (IL-17 knockout mice) as well as human experimental data indicate that Th17 and its signature cytokine IL-17 have a critical role in the pathogenesis of psoriatic disease. Th17 cells have been identified from the dermal extracts of psoriatic lesions. Subsequently, our research group has substantiated this observation that Th17 cells are enriched in the papillary dermis of psoriatic plaques and in freshly isolated effector T lymphocytes from the synovial fluid of PsA patients, and we have reported that the majority of these CD4 + IL-17+ T cells are of memory phenotype (CD4RO(+)CD45RA(-)CD11a(+)). Recent reports also suggest that the synovial tissue in psoriatic arthritis is enriched with IL-17R, and its most well recognized receptor IL-17RA is functionally active in psoriatic arthritis. In this review article, we have discussed the role of IL-17 in psoriatic disease and have narrated about the novel IL17/IL-17R antibodies currently in preparation for its therapeutic uses in autoimmune diseases.

[4] 
Dermatol Ther (Heidelb). 2014 Jan 23. [Epub ahead of print] Efficacy and Safety of Secukinumab in Chronic Plaque Psoriasis and Psoriatic Arthritis Therapy.
Gisondi P, Dalle Vedove C, Girolomoni G.
Author information
Abstract

Psoriasis is a chronic inflammatory skin disease affecting about 1-3% of the general population. Moderate-to-severe psoriasis is commonly associated with various comorbidities, including psoriatic arthritis (PsA) and cardio-metabolic disorders such as obesity, hypertension, diabetes, and metabolic syndrome. There is increasing recognition that systemic inflammation accompanies severe skin disease. Abnormal innate and adaptive immune responses in the skin are involved in pathogenesis. The cytokine interleukin (IL)-17A is produced by T helper 17 (Th17) cells, neutrophils, mast cells, and T cytotoxic 17 cells. IL-17 plays a key role in host defense against extracellular bacteria and fungi. IL-17A acts on keratinocytes to increase expression of chemokines involved in recruiting myeloid dendritic cells, Th17 cells, and neutrophils to the lesion site. IL-17A also induces the production of antimicrobial peptides and pro-inflammatory cytokines that,
in turn, may amplify and sustain immune responses in the skin. Blocking IL-17A improved psoriasis- like pathology in experimental models, and reduction in IL-17 signaling is part of the mechanism of action of tumor necrosis factor-α blockers. Three agents neutralizing IL-17 (i.e., secukinumab and ixekizumab) or antagonizing its receptor (i.e., brodalumab) are currently being tested for efficacy and safety in the treatment of plaque psoriasis and PsA. Secukinumab is a fully human IgG1 monoclonal antibody that selectively binds and neutralizes IL-17A whose efficacy in the therapy of chronic plaque psoriasis has been demonstrated in different phase II clinical trial. No new safety signals have emerged so far.


[6] 
Am J Chin Med. 2011;39(5):933-41. doi: 10.1142/S0192415X11009317.
Matrine suppresses production of IL-23/IL-17 and ameliorates experimental autoimmune encephalomyelitis.
Zhao X, Kan Q, Zhu L, Zhang GX.
Author information
Abstract

Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been suggested to possess immunomodulatory characteristics; however, whether it is effective in multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is not known. Our aim was to bridge this gap by investigating the possible therapeutic effects of MAT on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have found that, compared to the untreated controls, MAT-treated rats showed a significant decrease in clinical scores, in CNS infiltration of inflammatory cells (including CD4(+), CD8(+) T cells and macrophages) and demyelination. Furthermore, serum levels of IL-23 and IL-17 showed a marked reduction after MAT treatment, particularly in rats treated with higher doses of MAT. This study demonstrates that administration of MAT, as a natural compound, might be a novel therapy for autoimmune disorders
such as MS.

[7] J Ethnopharmacol. 2013 Jul 9;148(2):537-43. doi: 10.1016/j.jep.2013.05.001. Epub 2013 May 13.Protective effect of a Butea monosperma (Lam.) Taub. flowers extract against skin inflammation: antioxidant, anti-inflammatory and matrix metalloproteinases inhibitory activities.Krolikiewicz-Renimel I, Michel T, Destandau E, Reddy M, André P, Elfakir C, Pichon C.
Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:
Butea monosperma (Lam.) Taubert (Syn. Butea frondosa; family Fabaceae) is a common plant of the Indian continent (Das et al., 2011; Sharma and Deshwal, 2011). The brightly orange flowers of this plant are widely used in traditional medicine and more particularly for inflammatory disease.
AIM OF THE STUDY:
In vitro anti-inflammatory mechanism of a hydroethanolic extract of B. monosperma flowers (BME) and more specifically of an enriched fraction in butrin and isobutrin (BI) was studied using cell culture of Normal Human Keratinocyte, cells involved in the skin inflammatory.
MATERIALS AND METHODS:
Dried and crushed B. monosperma flowers were extracted with Ethanol/H2O (70/30 v/v). The butrin/isobutrin fraction was obtained by centrifugal Partition Chromatography (CPC). Experiments were conducted on UV-B treated normal human epidermis keratinocytes, cells involved in the skin inflammatory response. To evaluate extract anti-inflammatory activity, cytokines IL-1β, IL-6, IL-8, prostaglandin E2 and metalloproteinases MMP-1, -2, -9 and -10 were measured in the cells
supernatant.
RESULTS:
Our data clearly showed that hydroalcoholic B. monosperma flower extract was able to decrease the secretion of IL-1β, IL-6 and IL-8 pro-inflammatory cytokines of -32, -33 and -18% respectively. Interestingly, Prostaglandin E2 production and the secretion of MMP-1, -2, -9 and -10 were also inhibited. Same results were observed in presence of enriched fraction in butrin and isobutrin and confirmed the participation of these molecules in the anti-inflammatory activity.
CONCLUSION:
These results explain the anti-inflammatory activity of B. monosperma and confirm the interest to use it in traditional Indian medicine. Moreover, its metalloproteinases inhibitory activities coupled with its anti-inflammatory action also give anti-aging property to this plant.

[8]
J Pharm Pharmacol. 2012 Jun;64(6):882-7. doi: 10.1111/j.2042-7158.2012.01480.x. Epub 2012 Mar 27.
Total flavonoids of Bidens bipinnata L. a traditional Chinese medicine inhibits the production of inflammatory cytokines of vessel endothelial cells stimulated by sera from Henoch-Schönlein purpura patients.
Bo Y, Yuan LP, Zhang JJ, Meng DD, Jing H, Dai HJ.
Author information

Abstract
OBJECTIVES:
Bidens bipinnata L. is well known as a traditional antipyretic, anti-inflammatory and anti- rheumatic medicine in China. This study was designed to evaluate the role of total extracted flavonoids from B. bipinnata (TFB) in inhibiting the production of inflammatory cytokines.

METHODS:
Human umbilical vein endothelial cells (HUVEC) were used to examine the effect of TFB on the production of inflammatory cytokines. The supernatant interleukin (IL)-8, tumour necrosis factor (TNF)-α and nitric oxide (NO) levels of HUVEC were measured with ELISA methods. Nuclear factor- kappaB (NF-κB) and fractalkine expression was evaluated by RT-PCR and Western blot methods,respectively.

KEY FINDINGS:
We observed that IL-8, TNF-α and NO release of HUVEC incubated with sera from active Henoch- Schönlein purpura (HSP) was significantly increased. TFB intervention may significantly suppressed the supernatant IL-8, TNF-α and NO levels of HUVEC. Similarly, TFB obviously suppressed the NF-κB and fractalkine mRNA and protein expression.

CONCLUSIONS:
These results suggested that TFB may be useful for improving microvascular inflammation in HSP
patients.

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