The protease inhibitor cystatin C down‐regulates the release of IL‐β and TNF‐α in lipopolysaccharide activated monocytes

[摘要] HumancystatinC,amemberofthecysteineproteinase‐inhibitoryfamily,isproducedbyallnucleatedcellsandhasimportantrolesinregulatingnaturalimmunity.NematodehomologstohumancystatinChavebeenshowntohaveanti‐inflammatoryeffectsonmonocytesandtoreducecolitisinmice.InCrohn'sdisease,pathogenicactivatedmonocyteshelpdriveinflammatoryprocessesviathereleaseofproinflammatorycytokinesandchemokines.Inparticular,tumornecrosisfactor‐α–producinginflammatorymonocyteshaveacentralroleintheintestinalinflammationinpatientswithCrohn'sdisease.WeinvestigatedthepotentialofhumancystatinCtoregulatepathogenicactivatedmonocytesanditspotentialasanImmunomodulatorinCrohn'sdisease.WefoundthatcystatinCsignificantlydecreasedthelipopolysaccharide‐stimulatedreleaseandexpressionofinterleukin‐1βandtumornecrosisfactor‐αinmonocyteandperipheralbloodmononuclearcellculturesfromhealthydonors,whereasinterleukin‐6andinterleukin‐8levelswereunchanged.Asimilarreductionofinterleukin‐1βandtumornecrosisfactor‐αwasalsoseeninperipheralbloodmononuclearcellculturesfrompatientswithCrohn'sdisease,andinparticular,tumornecrosisfactor‐αwasreducedinsupernatantsfromlaminapropriacellculturesfrompatientswithCrohn'sdisease.FurtherinvestigationrevealedthatcystatinCwasinternalizedbymonocytesviaanactiveendocyticprocess,decreasedphosphorylationofthemitogen‐activatedproteinkinasepathwayextracellularsignal‐regulatedkinase‐1/2,andalteredsurfacemarkerexpression.TheabilityofcystatinCtomodulatethecytokineexpressionofmonocytes,togetherwithitsprotease‐inhibitoryfunction,indicatesthatmodulationofthelocalcystatinCexpressioncouldbeanoptioninfutureCrohn'sdiseasetherapy...

[学科分类] 生理学

[关键词] monocytes;cytokines;immunomodulator;inflammation;Crohn's disease