Innate immunity provides the initial defense against pathogen infection and is triggered by the microbial components of foreign pathogens, which are collectively known as pathogen-associated molecular patterns (PAMPs). Following recognizing of different PAMPs, host pattern-recognition receptors (PRRs) rapidly activate intracellular signaling cascades that lead to the induction of various inflammatory cytokines, chemokines, and type I interferons. The consequences of inflammatory cytokine effects can be favorable, leading to coordinate the elimination of pathogen and infected cells, or unfavorable, leading to inflammatory and autoimmune diseases [1,2]. Thus, PRR activation is a double-edged sword, and its mediated signaling is strictly and finely regulated at multiple levels to prevent inappropriate activation and excessive inflammation, thus achieving a balance between protective immunity and inflammatory pathology [3].

Interleukin-6 (IL-6) is a pleiotropic cytokine with crucial functions in immune response, haemopoiesis, acute phase response, and inflammation [4]. As early as 1986, IL-6 was found to be a B-cell differentiation factor that differentiates activated B-cells into immunoglobulin producing cells [5]. It was subsequently found that IL-6 is a regulator of acute-phase responses and a lymphocyte-stimulatory factor, and that rapid production of IL-6 contributes to host defense during infection and tissue injury [4,6]. IL-6 transmits signals through binding to a cell-surface receptor IL-6R (also known as IL-6Rα or CD126) and a second receptor protein, glycoprotein (gp) 130 (also known as IL-6Rβ or CD130) [7]. Once IL-6R signaling is initiated, several intracellular signaling pathways are activated, including the phosphoinositol-3 kinase (PI3K)–protein kinase B (PkB)/Akt pathway, Ras/mitogen activated protein kinases (MAPK) pathway, and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway, ultimately leading to modification of the expression of inflammatory cytokines and chemokines, such as IL-1β, IL-6, and IL-10 [7,8].

As lower vertebrates, fish also have the innate and adaptive immune responses, and their innate immune networks have important implications for innate immunity investigations in vertebrates. Similar to higher vertebrates, fish possess a range of signaling events for invading pathogens and conserved immune-relevant genes, which have received considerable attention for their role in improving understanding of immune system evolution. As a pleiotropic inflammatory cytokine, IL-6 has been characterized in several fish species [[9], [10], [11]]. Recent advances have documented that fish IL-6 plays a vital role in inflammatory response, driving lymphocyte differentiation, and inducing antimicrobial peptides, and might be a good immunopotentiator candidate for fish to prevent disease [10,11]. However, compared with mammalian, the transmitted signal pathways and precise molecular regulatory mechanism of IL-6 in fish are still poorly understood.

MicroRNAs (miRNAs) are a family of small non-coding RNA that directly interact with specific messenger RNAs (mRNAs) through base pairing, resulting in mRNAs degradation or translational repression, and play critical roles in many biological processes, including inflammation. For example, miR-146a, the first discovered to be involved in the regulation of the NF-κB pathway, has been characterized as a negative regulator of the inflammatory response by targeting and downregulating of IL-1 receptor–associated kinase 1 (IRAK1) and TNF receptor–associated factor 6 (TRAF6) [12]. Another extensively studied miRNA is miR-155, which has been shown involving in the negative regulation of Helicobacter pylori-induced inflammation by targeting myeloid differentiation primary response gene 88 (MyD88) [13]; miR-155 could also target the TAK1-binding protein 2 (TAB2) and inhibit the activation of NF-κB and MAPK, thereby acting as an anti-inflammatory agent [14]. In addition to regulating the signal molecules of PRR pathways, it is increasingly apparent that miRNAs can directly target inflammatory cytokines. Many interleukins have been found to be targeted by miRNAs. miR-365 and miR-142-3p were demonstrated to target IL-6 mRNA, thus reducing the endotoxin-induced mortality [15,16]. miR-466l could elevates IL-10 expression by preventing IL-10 mRNA degradation [17]. Moreover, TNF-α has been identified as a target of miR-125b [18]. Nevertheless, the molecular mechanisms of miRNAs in regulating interleukin and its mediated signaling pathways against pathogens remains largely unknown in fish.

Red drum (Sciaenops ocellatus) also known as spot-tail bass, redfish, or channel bass, belongs to Sciaenidae and is mainly farmed in the Atlantic Ocean and the Gulf of Mexico. As its rapid growth, strong environmental adaptability, and high nutritional value, S. ocellatus has been widely cultured and listed as one of the most important commercial fish in China. The species has been extensively studied in the whole-genome [19], transcriptome [20], and functional molecules with immunity [[21], [22], [23]], making S. ocellatus a new model organism for studying fish immune responses and comparative immunology. However, the frequency outbreaks of infectious disease have caused enormous mortality and economic losses, and thus promoting research on immune regulatory mechanisms of S. ocellatus. In this study, we identify IL-6 gene of S. ocellatus (named SocIL-6) and elaborate its role in inflammatory response following the infection of Vibrio harveyi, a typical gram-negative bacterium. Furthermore, we report a novel miRNA, Soc-miR-118, which suppresses the production of inflammatory cytokines through directly repression of IL-6, thus eliminating excessive inflammation reaction. These findings not only provide a new miRNA-mediated network of host-pathogen interactions, but also enrich the theory of comparative immunology.