Scientific Publications by FDA Staff
J Leukoc Biol 2012 Jan;91(1):147-58
TLR9 and TLR7 agonists mediate distinct type I IFN responses in humans and nonhuman primates in vitro and in vivo.
Puig M, Tosh KW, Schramm LM, Grajkowska LT, Kirschman KD, Tami C, Beren J, Rabin RL, Verthelyi D
Human I-IFNs include IFN-ß and 13 independently regulated subtypes of IFN-a (I-IFNs). TLR7 and -9 induce I-IFNs, but it is unknown whether their subtype repertoire is similar. This study used new PCR arrays that selectively amplify individual I-IFN subtype genes of human and nonhuman primates to characterize the TLR7- and -9-mediated IFN response in vitro and in vivo. We show that in human PBMCs, TLR7 agonists induce a rapid burst of I-IFN transcripts, consisting primarily of IFN-a1/13, -a2, and -a14. In contrast, TLR9 agonists, regardless of the type used (CpG C-, B-, or D-ODN), prompted slower but sustained expression of IFN-a1/13, -a2, -a7, -a8, -a10, -a14, -a16, and -a21. These qualitative differences were translated downstream as differences in the pattern of IFN-inducible genes. In macaque PBMCs, imiquimod produced a short burst of IFN mRNA, dominated by IFN-a8, whereas C- or D-ODN induced a greater than tenfold increase in transcripts for all I-IFN subtypes by 12 h of culture. Differences were more evident in vivo, where TLR7 and -9 agonists induced significantly different levels of I-IFN transcripts in skin. Although the rates of gene transcription differed significantly for individual TLR9 agonists, their IFN-a subtype signature was almost identical, indicating that the type of receptor dictates the quality of the I-IFN response in vitro and in vivo. These results may underlie the differential therapeutic effects of TLR7 and -9 agonists and should inform future clinical studies.
|Category: Journal Article|
|PubMed ID: #22058422||DOI: 10.1189/jlb.0711371|
|Includes FDA Authors from Scientific Area(s): Biologics Drugs|
|Entry Created: 2011-10-04||Entry Last Modified: 2015-06-03|