Grass carp TGF-beta 1 impairs IL-1 beta signaling in the inflammatory responses: Evidence for the potential of TGF-beta 1 to antagonize inflammation in fish

摘要

In the present study, effects of TGF-beta 1 on IL-1 beta signaling during inflammatory response were examined in grass carp. In grass carp head kidney leukocytes (HKLs), LPS significantly induced the mRNA expression of grass carp TGF-beta 1 (gcTGF-beta 1) and IL-1 beta, indicating the involvement of TGF-beta 1 and IL-1 beta in inflammatory process. Using anti-IL-1 beta antibody to neutralize the endogenous IL-1 beta, we found that stimulation of IL-1 beta mRNA expression by LPS was independent on IL-1 beta itself. Interestingly, recombinant gcTGF-beta 1 (rgcTGF-beta 1) suppressed basal and LPS-stimulated IL-1 beta mRNA expression in spite of immunoneutralizing endogenous IL-1 beta or not. Given that IL-1 beta receptor signaling molecule and natural IL-1 beta inhibitors are the important regulators in IL-1 beta signaling and activity, the effect of LPS on these molecules' expression was determined in HKLs. Results showed that LPS significantly enhanced the mRNA levels of IL-1 receptor type I (IL-1RI) and II (IL-1RII), IL-1R accessory protein (IL-1Racp) and novel IL-1 family member (nIL-1F). Moreover, the induction of IL-1RII, IL-1Racp and nIL-1F by LPS was IL-1 beta-dependent since IL-1 beta immunoneutralization abolished these inductions, implying the involvement of IL-1 beta auto-induction in these effects. Consistently, TGF-beta 1 could block basal IL-1RI and nIL-1F mRNA expression, and LPS-induced IL-1RI, IL-1Racp and nIL-1F mRNA expression, suggesting these molecules as the regulatory sites for TGF-beta 1 to modulate IL-1 beta signaling. Subsequent in vivo studies showed that bacterial challenge significantly up-regulated IL-1 beta mRNA expression with a rapid and transient pattern and TGF-beta 1 mRNA expression with a relatively time-delayed kinetics in head kidney. These expression patterns coincide with their pro-inflammatory and anti-inflammatory roles, respectively. As expected, rgcTGF-beta 1 could suppress bacterial-induced IL-1 beta mRNA expression, strengthening the anti-inflammatory role of TGF-beta 1 in vivo. Taken together, these results to our knowledge provide the first evidence for inducible TGF-beta 1 expression in inflammatory process, as well as the induction of inflammatory stimuli on IL-1 beta expression and signaling. In turn, TGF-beta 1 suppressed the proinflammatory process in vitro and in vivo presumably via interfering IL-1 beta expression and signaling in inflammatory response, highlighting the potential of TGF-beta 1 in the control of inflammation in fish. (C) 2016 Elsevier Ltd. All rights reserved.