H₂S transiently blocks IL‐6 expression in rheumatoid arthritic fibroblast‐like synoviocytes and deactivates p44/42 mitogen‐activated protein kinase

Abstract

Sulfur bath therapy represents the oldest form of treatment for patients with different types of rheumatic disorders. However, scientific reports about the beneficial effects of this form of therapy are controversial, rare and of poor scientific quality. Also, little is known about the role and underlying molecular mechanisms of H2S. Therefore, this topic encouraged us to investigate the influence of H2S on fibroblasts isolated from the synovial membrane of RA (rheumatoid arthritis) patients. FLSs (fibroblast-like synoviocytes) were treated with different concentrations of an exogenous H2S donor (NaHS). At defined time points, secretion of IL-6 was quantified by ELISA. Activation/deactivation of MAPKs (mitogen-activated protein kinases), p38 and p44/42 MAPK (ERK1/2) were confirmed by Western blot experiments. FLSs constitutively express and secrete large quantities of IL-6 and IL-8. Data provided prove that, in FLSs, constitutive as well as IL-1beta-induced expression of IL-6 is transiently and partially down-regulated by the short treatment of cells with low concentrations of NaHS. Another key finding is that H2S deactivates p44/42 MAPK (ERK1/2). Long-term exposure of FLSs to H2S provides stimulatory effects, leading to reinforced activation of p38 MAPK and ERK1/2 accompanied by upregulation of IL-6 expression. Presented data seem of importance for studying (patho-) physiological functions of H2S and also for re-evaluating sulfur spa therapy as one of the oldest forms of therapy for rheumatic disorders.

Exogenous hydrogen sulfide protects H9c2 cardiac cells against high glucose-induced injury by inhibiting the activities of the p38 MAPK and ERK1/2 pathways

“…The ERK1/2 activation has been shown to be increased (42)(43)(44)(45)(46), decreased (22,23,29,(47)(48)(49) or unaltered (50,51) following exposure to H 2 S. In the present study, we provide clear evidence that the activation of ERK1/2 contributes to HG-induced injury in H9c2 cells and that exogenous H 2 S protects H9c2 cells against HG-induced injury by inhibiting ERK1/2 activation, which is supported by our previous study [Dong et al (23)]. Although the mechanisms through which ERK1/2 induces either cell death or survival and the reasons for the differential effects induced by exogenous H 2 S on the activation of ERK1/2 are unclear, it is generally accepted that the duration and magnitude of ERK1/2 activation may be an important factor in determining cell survival or apoptosis (52).…”

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

“…However, whether the increase in synovial H 2 S synthesis represents an endogenous mechanism to promote inflammation or whether synthesis was elevated in response to joint injury as an anti-inflammatory response is unknown. Recently, Kloesch et al showed that in synviocytes isolated from RA patients, administration of a bolus of NaSH transiently decreased and then increased IL-1b-induced synthesis of IL-6 [67]. Mechanistic Perspective Whiteman & Winyard studies suggested that this was independent of NF-kB activation but dependent on ERK1/2 deactivation.…”

Balneoterapijos Efektyvumas Ir Perspektyvos

“…Nustatytas poveikis hormonams (didėja prieširdžių natruretinio peptido, mažėja renino aktyvumas, mažėja aldosterono gamyba, mažėja anti-diuretinio hormono, didėja dopamino, keičiasi AKTH, kortizolio kiekiai, didėja ß-endorfino, augimo hormono, norepinefrino, prolaktino), lipidams (padidėja didelio tankio lipoproteinų), citokinams (TNF-α,IL-1α IL-1β,IL-6, IFN-γ , IL-2, IL-4, EGF, TGF-β1), prostaglandinams (PGE 2, LTB 4, PGF 2 α), ląstelių populiacijoms (Langerhanso, T-ir B-, CD4+, CD4-, CD8+, CD8 ląstelėms), C-reaktyviam baltymui, haptoglobulinui, medžiagai P, matrikso metaloproteazėms (MMP-1, MMP-2, mažėja MMP-3, didėja MMP-8, MMP-9), poveikis oksidacinei/antioksidacinei sistemai (sumažinama reaktyvaus deguonies (ROS) ir azoto (RNS) atmainų, katalazės, superoksido dismutazės, gliutationo peroksidazės aktyvumas, sumažėja glikolizuoto hemoglobino, β-2-mikroglobulino, azoto oksido, galimai stimuliuojama opioidų sekrecija, modifikuojami SERT (serotonimo transporteriai) receptoriai, gerėja afinitetas SERT. Nustatyta, kad spa terapija didina į insuliną panašaus augimo faktoriaus-1 (IGF1), kuris stimuliuoja kremzlės metabolizmą, ir transformuojančio augimo faktoriaus-β (TGF-β) kiekius [20][21][22][23][24][25][26][27]31]. Šių citokinų, chemokinų, uždegimo/ oksidacijos biomarkerių kaitos pasekoje pastebimas teigiamas poveikis reumatologinėms ligoms, depresijai, psoriazei, lėtiniam/alerginiam rinosinusitui, kraujospūdžiui, lėtinei obstrukcinei plaučių ligai ir kitiems susirgimams [3].…”

“…M. Vitale, remdamasis "PubMed" duomenimis, pastebėjo, kad daugiausia balneoterapijos poveikio tyrimų 2000-2013 metais skirta uždegi-mui ir odai, mažiausiai -nervų sistemai ir ląstelių apoptozei [3]. Naujausi gydymo balneologinėmis procedūromis tyrimai patvirtina statistiškai reikšmingą pagerėjimą sergant: a) ankilozuojančiu spondilitu [49,50]; b) fibromialgija [26,51]; c) osteoartritu [52][53][54][55][56]; d) reumatoidiniu artritu [24,25]; e) psoriaze [57,69]; f ) venų varikoze [58][59][60]; g) esant apatinės nugaros dalies skausmams [61][62][63]. Falagas ir kt.…”