Macrolide antibiotics such as azithromycin or clarithromycin are known to have potent anti-inflammatory and immunomodulatory effects but these properties cannot be widely used due to a risk of bacterial resistance. We studied another polyketide antibiotic, structurally related manumycin A known as a streptomycete derived farnesyltransferase inhibitor with limited antibacterial effects, with respect to its potential regulation of mRNA expression of several genes associated with proinflammatory responses. Downregulation of mRNA for IL-6, TLR-8, IL-1 beta and IL-10 was found in THP-1 cells after 4h stimulation with TNF alpha in the presence of manumycin A and downregulated TLR-8 and EGR-1 genes were observed after 8h. Among the genes upregulated in response to manumycin were HMOX-1, TNFRSF10A, IL-1R1, TICAM2, NLRP12 after 4h and only IL-1R1 after 8h. Furthermore, manumycin A was found to inhibit IL-1beta, IL-6, and IL-8 production in TNF alpha stimulated THP-1 cells and peripheral blood monocytes in a dose dependent manner (0.25-1 μM of manumycin A) without affecting cell viability. Cell viability of blood monocytes decreased by about 30% at manumycin A doses of 2-5 μM. Manumycin A also inhibited IL-18 release from THP-1 cells, while in cultures of blood monocytes, this cytokine was not detectable. That manumycin A mediated downregulation of proinflammatory genes in human monocytes confirmed by a measurement of cytokine levels in culture supernatants, together with a very limited effect on cell viability, might suggest potential anti-inflammatory properties of this polyketide antibiotic.

Department of Clinical and Transplant Immunology Institute for Clinical and Experimental Medicine Videnska 1958 14021 Prague Czech Republic

Institute of Microbiology Academy of Sciences of the Czech Republic Videnska 1083 142 20 Prague Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc17000850

003      

CZ-PrNML

005      

20190703140851.0

007      

ta

008      

170103s2016 ne f 000 0|eng||

009      

AR

024    7_

$a 10.1016/j.imlet.2015.11.010 $2 doi

024    7_

$a 10.1016/j.imlet.2015.11.010 $2 doi

035    __

$a (PubMed)26602157

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a ne

100    1_

$a Brabcová, Eva $u Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic. $7 xx0212445

245    10

$a Manumycin A downregulates release of proinflammatory cytokines from TNF alpha stimulated human monocytes / $c E. Cecrdlova, K. Petrickova, L. Kolesar, M. Petricek, A. Sekerkova, V. Svachova, I. Striz,

520    9_

$a Macrolide antibiotics such as azithromycin or clarithromycin are known to have potent anti-inflammatory and immunomodulatory effects but these properties cannot be widely used due to a risk of bacterial resistance. We studied another polyketide antibiotic, structurally related manumycin A known as a streptomycete derived farnesyltransferase inhibitor with limited antibacterial effects, with respect to its potential regulation of mRNA expression of several genes associated with proinflammatory responses. Downregulation of mRNA for IL-6, TLR-8, IL-1 beta and IL-10 was found in THP-1 cells after 4h stimulation with TNF alpha in the presence of manumycin A and downregulated TLR-8 and EGR-1 genes were observed after 8h. Among the genes upregulated in response to manumycin were HMOX-1, TNFRSF10A, IL-1R1, TICAM2, NLRP12 after 4h and only IL-1R1 after 8h. Furthermore, manumycin A was found to inhibit IL-1beta, IL-6, and IL-8 production in TNF alpha stimulated THP-1 cells and peripheral blood monocytes in a dose dependent manner (0.25-1 μM of manumycin A) without affecting cell viability. Cell viability of blood monocytes decreased by about 30% at manumycin A doses of 2-5 μM. Manumycin A also inhibited IL-18 release from THP-1 cells, while in cultures of blood monocytes, this cytokine was not detectable. That manumycin A mediated downregulation of proinflammatory genes in human monocytes confirmed by a measurement of cytokine levels in culture supernatants, together with a very limited effect on cell viability, might suggest potential anti-inflammatory properties of this polyketide antibiotic.

650    _2

$a antibakteriální látky $x farmakologie $7 D000900

650    _2

$a antiflogistika $x farmakologie $7 D000893

650    _2

$a buněčné linie $7 D002460

650    _2

$a cytokiny $x genetika $x metabolismus $7 D016207

650    _2

$a protein 1 časné růstové odpovědi $x genetika $x metabolismus $7 D051766

650    _2

$a regulace genové exprese $x účinky léků $7 D005786

650    _2

$a lidé $7 D006801

650    _2

$a imunomodulace $7 D056747

650    _2

$a zánět $x farmakoterapie $x imunologie $7 D007249

650    _2

$a monocyty $x účinky léků $x imunologie $7 D009000

650    _2

$a polyeny $x farmakologie $7 D011090

650    _2

$a polynenasycené alkamidy $x farmakologie $7 D053284

650    _2

$a messenger RNA $x genetika $7 D012333

650    _2

$a receptory interleukinu-1 $x genetika $x metabolismus $7 D017472

650    _2

$a toll-like receptor 8 $x genetika $x metabolismus $7 D051200

650    _2

$a TNF-alfa $x metabolismus $7 D014409

655    _2

$a časopisecké články $7 D016428

700    1_

$a Petříčková, Kateřina $u Institute of Microbiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic. $7 xx0104744

700    1_

$a Kolesár, Libor $u Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic. $7 xx0142511

700    1_

$a Petříček, Miroslav $u Institute of Microbiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic. $7 xx0101687

700    1_

$a Sekerková, Alena $u Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic. $7 xx0204822

700    1_

$a Švachová, Veronika $u Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic. $7 xx0254626

700    1_

$a Stříž, Ilja, $u Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic. Electronic address: ilja.striz@ikem.cz. $d 1958- $7 jn20000402309

773    0_

$w MED00002200 $t Immunology letters $x 1879-0542 $g Roč. 169, č. - (2016), s. 8-14

856    41

$u https://pubmed.ncbi.nlm.nih.gov/26602157 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y a $z 0

990    __

$a 20170103 $b ABA008

991    __

$a 20190703141041 $b ABA008

999    __

$a ok $b bmc $g 1179990 $s 961417

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2016 $b 169 $c - $d 8-14 $e 20151118 $i 1879-0542 $m Immunology letters $n Immunol Lett $x MED00002200

GRA    __

$a NT13012 $p MZ0

LZP    __

$a Pubmed-20170103