Zinc modulates the innate immune response in vivo to polymicrobial sepsis through regulation of NF-κB

Abstract

Zinc is an essential element that facilitates coordination of immune activation during the host response to infection. We recently reported that zinc deficiency increases systemic inflammation, vital organ damage, and mortality in a small animal model of sepsis. To investigate potential mechanisms that cause these phenomena, we used the same animal model and observed that zinc deficiency increases bacterial burden and enhances NF-kappaB activity in vital organs including the lung. We conducted further studies in the lung to determine the overall impact of zinc deficiency. At the molecular level, NF-kappaB p65 DNA-binding activity was enhanced by zinc deficiency in response to polymicrobial sepsis. Furthermore, expression of the NF-kappaB-targeted genes IL-1beta, TNFalpha, ICAM-1, and the acute phase response gene SAA1/2 were elevated by zinc deficiency. Unexpectedly, the amount of NF-kappaB p65 mRNA and protein was increased in the lung including alveolar epithelia of zinc-deficient mice. These events occurred with a significant and concomitant increase in caspase-3 activity within 24 h of sepsis onset in zinc-deficient mice relative to control group. Short-term zinc supplementation reversed these effects. Reconstitution of zinc deficiency in lung epithelial cultures resulted in similar findings in response to TNFalpha. Taken together, zinc deficiency systemically enhances the spread of infection and NF-kappaB activation in vivo in response to polymicrobial sepsis, leading to enhanced inflammation, lung injury, and, as reported previously, mortality. Zinc supplementation immediately before initiation of sepsis reversed these effects thereby supporting the plausibility of future studies that explore zinc supplementation strategies to prevent sepsis-mediated morbidity and mortality.

Pathological study of pulmonary toxicity induced by intratracheally instilled Asian sand dust (Kosa): Effects of lowered serum zinc level on the toxicity

“…Increased inflammation and organ damage under zinc deficient condition were also reported in a murine polymicrobial sepsis model [41]. Zn was previously reported to influence inflammation by the production and signaling of numerous inflammatory cytokines including TNF and IL-1b in a variety of cell types [23][24][25]42]. Immunohistochemistry demonstrated a larger number of Cytoplasmic vacuolar changes of enlarged macrophages containing fine ASD particles were observed in lung lesions in this study; the changes appeared to be more prominent in mice with low levels of serum Zn.…”

“…Defective membrane repair is associated with compromised wound healing, muscular dystrophy, and cardiovascular disease onset [20]. Moreover, zinc has been reported to be important in airway homeostasis [21] and influence inflammation by the production and signaling of numerous inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1b in a variety of cell types [22][23][24][25].…”

Zinc: dietary intake and impact of supplementation on immune function in elderly

“…Zinc in vitro (10 μM) improves the development of CD34+ cell progenitors towards NK cells both in young (expressing CD56+ CD16− phenotype) and old age (expressing CD56− CD16+ or CD56+ CD16+ phenotypes), via increased expression of GATA-3 transcription factor (Muzzioli et al 2009). Moreover, several studies in old animals and humans describe decreased NK cell cytotoxicity related to zinc deficiency ) through different mechanisms involving NF-kB or Ap-1 transcriptional factors or A20 protein (Prasad 2007;Bao et al 2010). In vitro (1 μM) and in vivo zinc treatments (12 mg Zn ++ /day) for a short period (1 month) induce complete recovery of NK cell cytotoxicity both in old mice and humans (Mocchegiani et al 1995;Mariani et al 2008).…”

“…Various mechanisms of action of zinc upon the immune system have been well elucidated. Both direct and indirect mechanisms of zinc are involved in affecting the immune response in ageing from inducing DNA proliferation, to maintaining membrane stability, to restoring Th1/Th2 paradigm up to preventing apoptosis, via activation of nuclear factors NF-kB and AP-1, caspase-3 inhibition or induction of A20 protein with subsequent reduction of proinflammatory cytokines (Table 2) (Shankar and Prasad 1998;Mocchegiani et al 2000;Prasad 2007;Bao et al 2010;Prasad et al 2011). The most intriguing mechanism of zinc upon the immune system is however the existing interrelationship among pro-inflammatory cytokines (IL-6)-Metallothioneins (MT)-Nitric Oxide (NO)-PARP-1 taking into account that IL-6 promotes MTmRNA induction, NO is involved in zinc release by MT and PARP-1 (a nuclear enzyme codified by two zinc finger motifs) prevents apoptosis with subsequent cellular genomic stability (Mocchegiani et al 2000).…”

“…Therefore, zinc supplementation may be of benefit in prevention or in reducing the risk or in delaying the appearance of diseases and the subsequent disability. For specific references see: Shankar andPrasad (1998), Fraker andTelford (1997), Mocchegiani et al (1998), Mocchegiani et al (2000), Prasad et al (2006), Prasad (2007), Haase and Rink (2009a, b), Bao et al (2010) and Prasad et al 2011) Evidences of the usefulness of zinc supplementation for immunity in the elderly began to emerge three decades ago with however inconsistent data on its beneficial effect upon the immune efficiency due to different doses and duration of zinc treatment as well as the form of zinc to be supplemented (Mocchegiani et al 2008d). Although zinc was used at the doses recommended by RDA (from 10 up to 40 mg/day) (U.S. Department of Agriculture 1996) improvements of both innate and adaptive immune responses are not so exciting and also contradictory.…”