Te kikorangi metilīni me te tuku tohu mumura: ngā inflammasome, IL-6, me STAT3

Whakaarohia e toru ngā taiwhanga e pūrongo ana he ārai mumura te pūhui kikorangi kotahi. Ka whakaatu tētahi i te hekenga o IL-1beta mai i ngā pūtau kaihoromi. Ka whakaatu tētahi i te hekenga o te whākōkī iNOS i taua momo pūtau anō. Ka whakaatu tētahi i te hekenga o IL-6 i te toto me te hekenga o te hohe o STAT3 i te roro. He māmā te whakakotahi i ēnei hei kerēme kotahi. Engari mā taua whakakotahitanga e huna ai te kitenga.

Nō tētahi ariā tuku tohu rerekē ia hua, ā, kei ia ariā tōna ake whakaoho, hipanga whakahiato, me te inenga putanga. Ka pā te kikorangi metilīni ki ia ariā i tētahi wāhi rerekē. He pātai motuhake mēnā ka whakapai ake tētahi o ēnei i tētahi putanga hauora; kei tā mātou tirohanga whānui ki te kikorangi metilīni me te mumura taua pātai e kōrerotia ana. Ka aro tēnei whārangi ki ngā ara tuku tohu.

Ara 1: te whakahiato inflammasome me caspase-1

He anga pūmua te inflammasome, ka hangaia ina hiahiatia ki roto i tētahi pūtau myeloid. Ko ōna wāhanga he pūoko, he pūmua tūhono ko ASC te ingoa, me tētahi whākōkī whakatutuki ko caspase-1 te ingoa. Kia oti te whakahiato, ka tapahia e caspase-1 a pro-IL-1beta me pro-IL-18 kia puta ai ō rāua āhua ka tukuna ki waho o te pūtau, ā, ka taea hoki te whakaoho i te pyroptosis, he momo matenga pūtau e pā ana ki te mumura. Mā te pūoko e tautuhi te momo: ka urupare a NLRP3 ki ngā tioata me ngā tāoke hanga kōhao pērā i nigericin me ATP; ka urupare a NLRC4 ki te flagellin huakita; ka urupare a AIM2 ki te DNA whenu-rua kei te wai o roto i te pūtau; ā, ka urupare te ara kore-tikanga ki te lipopolysaccharide kei roto i te pūtau.

E rua ngā tohu e hiahiatia ana mō te whakahohe. Ko te tohu tuatahi he whakarite: mā tētahi rāpoi here ki te pūwhiwhi āhua-Toll e kōkiri te tuhinga ira o NLRP3 me pro-IL-1beta e whakawhirinaki ana ki NF-kB, kia wātea ai ngā wāhanga. Ko te tohu tuarua he whakahiato: mā tētahi whakaoho tuarua ka whakakotahi a ASC hei huinga ira, ka tapahia a caspase-1 hei tōna kongakonga p20, ā, ka tukuna te IL-1beta p17 kua maoa. E mōhiotia ana ko ngā momo hāora tauhohe o ngā pungao me te whakaurunga tioata ētahi āhuatanga e whai wāhi ana ki te tohu tuarua mō NLRP3.

I whakamātauhia te kikorangi metilīni i ngā tohu e rua i te rangahau pūtau kaihoromi o 2017 mō te aukati whānui i ngā inflammasome. I ngā pūtau kaihoromi nō te hinu wheua kiore kua whakaritea ki te lipopolysaccharide, nā nigericin, ATP, me ngā tioata monosodium urate i whakaoho te tukunga o IL-1beta me caspase-1, me te hanganga o ngā ira ASC. Nā te kikorangi metilīni i te 20 ki te 200 micromolar i whakaiti ēnei mea e toru katoa i runga i te nui o te horopeta, me te kore e whakamate i ngā pūtau. I kitea taua tauira anō ki te flagellin me Salmonella mō NLRC4, te DNA whenu-rua me Listeria mō AIM2, me te lipopolysaccharide i whakaurua mā te whakawhiti rāpoi, te E. coli ora rānei, mō te ara kore-tikanga. Kāore te pūhui anake i whakaoho i te tukunga, ā, kāore ngā pereti whakataurite i whakaatu i tētahi pānga ārai huakita, nō reira kei te urupare a te rauropi manaaki te hua.

I ngā hipanga o mua, e toru ngā pānga wawao i inea. I heke te superoxide pungao i whakaohohia e rotenone i te aroaro o te kikorangi metilīni, ā, i heke anō te tukunga IL-1beta i kōkirihia e rotenone. I heke te whakaurunga o ngā pirepire kōrekoreko, e hāngai ana ki te hekenga o te kaihoromi pūtau i mua i te rongo i ngā tioata. I whakaatu tētahi pūnaha pūrongo e kōkirihia ana e te kaiwhakatairanga ira NLRP3 me ōna wāhi NF-kB e rua i te hekenga o te hohe i te aroaro o te kikorangi metilīni, engari kāore tētahi kaiwhakatairanga ira kua poroa, kāore nei aua wāhi, i urupare. I tētahi ngongo kāore he pūtau, i whakaiti tika hoki te kikorangi metilīni i te hohe o te caspase-1 tangata i hangaia mā te hangarau whakakotahi ira. Ahakoa i tāpirihia te pūhui i te wā whakarite anake, i te wā whakahohe anake rānei, i heke tonu te tukunga o IL-1beta, IL-18, me caspase-1, nō reira e whai wāhi ana ngā hipanga e rua.

I hāngai ngā whakamātautau kiore ki tēnei pānga kōwhiri. Nā tētahi horopeta lipopolysaccharide whakamate i whakamate ngā kiore whakataurite i roto i ētahi hāora, engari nā te kikorangi metilīni i whakapai ake te oranga tonutanga; i heke te IL-1beta i te kōhao puku, engari kāore te IL-6 i taua wai anō i heke. I tētahi tauira mumura kiriuhi puku nā Listeria, i heke te IL-1beta i te kōhao puku, engari kāore te tapeke o ngā pūtau i rerekē. I rite te whanonga o ngā monocyte tangata THP-1 ki tō ngā pūtau kaihoromi kiore puta noa i ngā momo inflammasome e whā. Ka whakamārama tētahi hua inflammasome i te whakamaotanga o IL-1beta me IL-18, ehara i te mea i ia cytokine katoa. Koia hoki te take e whakautu ai te āhua o ngā pūtau ārai mate o te roro i ngā whakamātautau microglia me ngā astrocyte i tētahi pātai rerekē i tō te whakahiato anga pūmua.

Ara 2: te tuhinga ira iNOS mā te here a NF-kB me STAT1

Ko te whākōkī hanga waikura hauota ka taea te whakaoho, arā ko iNOS, he tino iti ina noho whakatā te pūtau, ā, ka tuhia tōna ira ina hiahiatia. Ko te ara matua e kōkiri ai te lipopolysaccharide i tēnei ko te wāwāhitanga o IkB-alpha, whai muri ko te tāpiritanga rōpū phosphate ki NF-kB me tōna urunga ki te karihi. Ko te ara matua e kōkiri ai te interferon-gamma ko te tāpiritanga rōpū phosphate ki STAT1 e te kinase Janus, whai muri ko te urunga o STAT1 ki te karihi. Kātahi ka here ia tauwehe ki tōna wāhi i te kaiwhakatairanga ira iNOS. He wāhi whakahaere motuhake te hohe o te whākōkī me te whakaoho ira, ā, ka taea e tētahi rongoā te pā ki tētahi, ki ngā mea e rua rānei.

Nā te rangahau o 2015 mō te whakaoho iNOS i ngā pūtau kaihoromi me ngā kiore whai tāoke o roto i te toto i whakatau te pānga ki te karere ira. I ngā pūtau RAW 264.7 me ngā pūtau kaihoromi kiore i tangohia tōtikatia, nā te 1 micromolar kikorangi metilīni i tukuna 30 meneti i mua i te lipopolysaccharide, te interferon-gamma, ngā mea e rua rānei, i whakaiti te pūmua me te mRNA iNOS puta noa i te 8 ki te 24 hāora. I iti iho hoki te nitrite i te wai whakatipu, ā, kāore te ora o ngā pūtau i heke. I ngā kiore i tukuna ki te 25 mg per kg lipopolysaccharide, nā tētahi horopeta kotahi o te 5 mg per kg i tukuna kotahi hāora i mua i whakaiti te pūmua me te mRNA iNOS i te pūkahukahu, te ate, me te manawa.

Ko te kōrero motuhake ko ngā mea kāore i rerekē. I mau tonu te wāwāhitanga o IkB-alpha, te tāpiritanga rōpū phosphate ki NF-kB, te tāpiritanga rōpū phosphate ki STAT1, me te kohikohinga o aua tauwehe e rua i te karihi. I puta te aukatinga i te hipanga whai muri: i whakaatu ngā tangohanga karihi i te iti iho o te here a NF-kB ki tōna wāhanga DNA i muri i te lipopolysaccharide, me te iti iho o te here a STAT1 i muri i te interferon-gamma. Nā te whakamātautau whakapūmau ārai mate o te chromatin i whakaū te iti iho o te noho o aua tauwehe e rua ki te kaiwhakatairanga ira iNOS i roto i ngā pūtau. I heke hoki te tauwehe whakamate puku alpha, e whakamahia ana hoki e tōna kaiwhakatairanga ira a NF-kB. I whakahohehia ngā tauwehe, ā, i tae atu ki te karihi, engari he ngoikore tō rāua here ki te DNA whāinga.

Kia mōhio ki te rerekētanga i te ara 1. E pā ana tēnei ki te here o te tauwehe ki te DNA, e whakamahi ana i STAT1, ehara i STAT3, ā, ko ngā putanga ka inea ko te mRNA, te pūmua, me te nitrite, ehara i ngā ira ASC me ngā kongakonga caspase-1. Mā tā mātou mahere o ngā whāinga kikorangi metilīni puta noa i ngā tauira pūtau e pupuri motuhake ai tēnei taumata tuhinga ira i ngā inenga tika o ngā whākōkī me ngā pungao.

Ara 3: te IL-6 i te serum me te whakahohe STAT3 i ngā kiko

Ka tuku tohu a IL-6 mā te whānau pūwhiwhi gp130 ki te raupapa kinase Janus ki STAT3. Ka takirua a STAT3 kua tāpirihia he rōpū phosphate, ka uru ki te karihi, ka kōkiri i ngā hōtaka mumura. He whāinga hoki a IL-6 ake nā NF-kB, nō reira ka hanga ēnei e rua i tētahi koropiko whakahoki tohu, e kīia ana i te nuinga o te wā ko te tuaka IL-6 ki STAT3. Ko ngā inenga putanga paerewa ko te IL-6 i te serum i ngā hipanga o mua, te ōwehenga o STAT3 kua tāpirihia he rōpū phosphate ki te tapeke STAT3, me ngā whākōkī whakatutuki pērā i iNOS me COX2 i ngā hipanga o muri.

I inea te tuaka puta noa i ngā wāhanga o te tinana i te rangahau kiore o 2023 mō IL-6 me STAT3 i muri i te lipopolysaccharide. I whiwhi ngā kiore toa C57BL/6 i te 1 mg per kg lipopolysaccharide ia rā mō te toru rā, me te 5, te 10 mg per kg rānei o te kikorangi metilīni 30 meneti i muri i ia horopeta. I te rā tuatoru, he iti iho te IL-6 i te serum i ngā rōpū kikorangi metilīni e rua i tō te rōpū lipopolysaccharide anake, engari kāore te nuinga o ērā atu cytokine i te huinga whakamātautau i rerekē nā te maimoatanga. He iti iho ngā ōwehenga o STAT3 kua tāpirihia he rōpū phosphate ki te tapeke STAT3 i te kiri roro, te hippocampus, me te kiri taringa. I iti iho hoki te whakapokea Iba-1 o ngā microglia, i iti iho a iNOS me COX2, ā, i āhua whakaitihia te ngaronga taumaha.

E rua ngā whakatūpato e tika ana i konei. Ko te iti iho o IL-6 i te serum me te iti iho o te tāpiritanga rōpū phosphate ki STAT3 i ngā kiko e hāngai ana ki te whakarerekētanga o te tuaka, engari kāore e tautuhi motuhake i te wāhi matua i pāngia. Ka taea e te iti iho o te cytokine i ngā hipanga o mua, te iti iho o te tuku tohu a te pūwhiwhi, te rerekētanga rānei o te hohe phosphatase, te whakaputa i taua ōwehenga anō. Waihoki, ko te taumaha i roto i ngā rā e toru o tētahi whakaoho whakapeka he inenga putanga mō te kararehe katoa, ehara i te kaute tohu māuiui, i te kaute whakaheke māuiui rānei. Ka tāpiri tēnei i te horopaki ki tua atu i tētahi whakamātautau blot, me te kore e huri i tētahi hua tuku tohu hei kerēme maimoatanga. E rere whakarara ana te matū motuhake o te whakahaere hāoratanga-whakahekenga i ngā pungao ki tēnei kōrero cytokine, ā, kaua ēnei e whakakotahitia.

Te whakataurite ara: ngā wāhi wawao me ngā inenga putanga

Ka aukati te ripanga i ngā whakawhitinga hē e toru. Kāore tētahi hua ira ASC e whakaū i tētahi hua STAT3. Kāore tētahi hua mō STAT1 ki te kaiwhakatairanga ira iNOS e whakaū i tētahi hua STAT3, ahakoa nō te whānau STAT ngā pūmua e rua. Kāore tētahi hua IL-6 i te serum e whakaū i te hekenga o te whakahiato inflammasome: i te whakamātautau kōhao puku i heke a IL-1beta, engari kāore a IL-6 i heke. Me whai ia rārangi i tōna ake whakaoho me tōna ake inenga putanga. Koia te take, ina pānuitia ngā rangahau kikorangi metilīni mō ngā pūtau, ngā kararehe, me ngā whakamātautau haumanu, me whakahāngai ia kerēme ki te taumata i inea.

Kāore tētahi o ēnei e whakapūmau i te horopeta, te haumaru, te painga rānei mō te tangata. He whakaoho kua whakahaerehia ngā tauira lipopolysaccharide hei whakamātau i tētahi tikanga, ehara i te tāruatanga o te māuiui mauroa. Waihoki, ko te tuku horopeta i te taha o te whakaoho he whakamātau i te ārai i tētahi panonitanga ka whakaohohia, ehara i te whakahuri i tētahi mate kua tau kē. Kia noho motuhake tēnei kōrero tikanga i ngā putanga mō ngā tūroro, ā, me aromatawai ia kerēme hauora mā te rangahau tūroro e tautoko ana i taua kerēme.