The calcineurin inhibitor RCAN1 is involved in cultured macrophage and in vivo immune response

Abstract

Studies on the role of regulator of calcineurin 1 (RCAN1) in immunity are limited, but have demonstrated an involvement in T-lymphocyte function. Here, we expand these studies to macrophages and in vivo infection. The treatment of RAW and primary mouse macrophages with lipopolysaccharide from Escherichia coli strongly induced RCAN1 isoform 4 (RCAN1-4), but not isoform 1. RCAN1-4 induction involved calcium, calcineurin, and reactive oxygen species. Subsequent analysis with whole bacteria including gram-negative E. coli and gram-positive Staphylococcus aureus revealed strong RCAN1-4 inductions by both, and where tested, dependence on calcium. Staphylococcus aureus cell wall components peptidoglycan and lipoteichoic acid also strongly induced RCAN1-4. In vivo, a significant induction in the proinflammatory cytokines monocyte chemotactic protein-1, interleukin-6, interferon-γ, and tumor necrosis factor-α was observed in knockout (KO) lung vs. wild-type (WT) mice 7 days after nasal infection with Fransicella tularensis. This induction was not accompanied by a significant increase in F. tularensis burden in the KO lung. Additionally, a modest increase in respiratory burst activity in KO vs. WT macrophages was observed. Combined, these studies indicate that RCAN1 is involved in macrophage and the overall in vivo immune response, and provide additional evidence that RCAN1 plays an important role in cell immunity and infectious disease.

Regulator of Calcineurin 1 in Periodontal Disease

“…The data of the present study show that the Gram-negative putative periodontal pathogen P. gingivalis increases the expression of rcan1 as much as VEGF, which is one of the main regulators of rcan1 . This and other results indicate that TLR4 receptors may be involved in the regulation of rcan1 [ 34 ]. Furthermore, the observed phenomenon might display a short-term mechanism that limits the early immune response towards P. gingivalis , thus avoiding any collateral damage due to an overreacting inflammation.…”

“…Rcan1 expression is mediated through numerous stimuli including calcium-elevating agents and cell receptor agonists like VEGF and thrombin [ 33 ]. Moreover, expression of rcan1 can be induced by Gram-positive and Gram-negative bacteria [ 34 ]. The data of the present study show that the Gram-negative putative periodontal pathogen P. gingivalis increases the expression of rcan1 as much as VEGF, which is one of the main regulators of rcan1 .…”

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

“…Previous work has focused on the role of RCAN1 in the production of various inflammatory cytokines in response to immunological stimuli (45). However, the biological implications of RCAN1 during infection remain poorly understood.…”

RCAN1 and Its Potential Contribution to the Down Syndrome Phenotype

“…Induction of inflammatory mediators was also reduced and there was a marked reduction in leukocyte infiltrate in the heart, liver and lungs [152]. Another study found that following infection with the bacteria Fransicella tularensis, induction of proinflammatory cytokines including MCP1, IL6, IFNγ, and TNFα was significantly higher in Rcan1-deficient spleen and lung [153]. All this suggests that over-expression of RCAN1 is protective.…”