For each of the stimuli used, a specific response pattern was found and the correlation cluster shows clear and distinct groups. The results support the concept of miRNAs acting in groups. Moreover, closely related miRNAs were found to react quite similar to the stimuli applied in our study. However, when inspecting the genomic origin of the miRNAs, we could not find these clusters resulting from operon-like gene structures that are transcribed from a common promoter as previously reported. In this context, it is important to point out, that until now, it has not been experimentally verified whether the previously predicted operonic organization of miRNA loci have a generalized functional significance. To assess the impact of the presented miRNA patterns, three exemplary miRNAs were selected for further analysis of their impact on potential target transcripts, associated to inflammatory processes: hsa-miR-129-5p, hsa-miR-146a and hsa-miR-378. Several studies reported that miR-146a is associated to the immune response, e.g. being upregulated in response to microbial components and pro-inflammatory cytokines while additional data indicated that miR-146a inhibits TRAF6 and IRAK1 directly. We could support this observation by an in silico prediction of targets for miR-146a using 3 different algorithms as well as by experimental approaches ex vivo and in vitro: i) we observed miR-146a as upregulated in response to stimulation of primary monocytes with TNF-a or LPS and ii) we observed an upregulation of TRAF6 and IRAK1 in the myelomonocytic THP-1 cell line after blocking miR-146a by transfection of anti-miR-146a in the presence of TNF-a. Generally, in silico target prediction approaches should be undertaken with caution, however, this finding documents the validity of the prediction tools as well as our experimental application of anti-miRNAs, when the expected endogenous level of the investigated miRNA is relatively high. The observed upregulation of miR-146a in response to several pro-inflammatory stimuli, combined with our findings on inhibitory effects of miR-146a on various inflammation-associated genes could indicate that miR146a may act as a regulator for tolerance to several proinflammatory/PAMP stimuli, which is supported by findings on its role as a negative regulator of innate immune signaling, findings on establishment of endotoxin tolerance in monocytes and findings on desensitizing cells to TLR2-dependent activation.. Additionally, the concept of miR-146a regulating immune response was supported by a study documenting its potential relevance for adaptive immunity. In this context, it has to be taken into consideration that the presented experimental setup does not allow to exclude differential miRNA responses which are the result of the different stimulatory potential exhibited by the employed stimuli. Consequently, the patterns can be attributed to different stimulatory potential, to specific response mechanisms or to a combination of both. Based on its signature similarity to miR-146a, miR-378 was selected to be further analyzed on target gene level. Interestingly, miR-378 exhibited this similarity on target-gene level as well: 97 of 117 target genes showed regulation in the same direction, supporting the hypothesis of miRNAs acting in functional clusters. The observed similarity to miR-146a may also indicate similar functional role in controlling the tolerance to microbial patterns. As a representative of the MDP-response cluster, miR-129-5p was selected. In contrast to all other miRNAs investigated, miR129-5p was the only miRNA that was regulated exclusively in response to MDP stimulation and showed no overall similarities to miRNAs in other clusters.