Chronic inhibition of cyclooxygenase-2 attenuates antibody responses against vaccinia infection

Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Vaccine (Impact Factor: 3.62). 11/2009; 28(5):1363-72. DOI: 10.1016/j.vaccine.2009.11.005
Source: PubMed


Generation of optimal humoral immunity to vaccination is essential to protect against devastating infectious agents such as the variola virus that causes smallpox. Vaccinia virus (VV), employed as a vaccine against smallpox, provides an important model of infection. Herein, we evaluated the importance cyclooxygenase-2 (Cox-2) in immunity to VV using Cox-2 deficient mice and Cox-2 selective inhibitory drugs. The effects of Cox-2 inhibition on antibody responses to live viruses such as vaccinia have not been previously described. Here, we used VV infection in Cox-2 deficient mice and in mice chronically treated with Cox-2 selective inhibitors and show that the frequency of VV-specific B cells was reduced, as well as the production of neutralizing IgG. VV titers were approximately 70 times higher in mice treated with a Cox-2 selective inhibitor. Interestingly, Cox-2 inhibition also reduced the frequency of IFN-gamma producing CD4(+) T helper cells, important for class switching. The significance of these results is that the chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), and other drugs that inhibit Cox-2 activity or expression, blunt the ability of B cells to produce anti-viral antibodies, thereby making vaccines less effective and possibly increasing susceptibility to viral infection. These new findings support an essential role for Cox-2 in regulating humoral immunity.

Download full-text


Available from: Elizabeth P Ryan, Oct 13, 2015
26 Reads
  • Source
    • "The effect of COX inhibition on antibody production in an infectious scenario has revealed conflicting results. During vaccinia virus infection, deletion of COX-2 resulted in decreased levels of several subclasses of IgG due to failure of immunoglobulin class-switching (Bernard et al., 2010). Similarly, pathogen-specific antibody production was decreased by COX-2 inhibition during Mycobacterium bovis-induced arthritis (Turull and Queralt, 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Experimental Lyme arthritis is an inflammatory arthritis caused by infection of mice with the spirochete, Borrelia burgdorferi. It recapitulates many of the disease parameters seen in human patients with Lyme arthritis, and thus serves as a model system for the investigation of disease pathogenesis. While much progress has been made in defining components of the immune response to Borrelia infection, an overall understanding of the host response leading to arthritis resistance or susceptibility remains elusive. In this review, we will focus on recent advancements of our understanding of the roles of eicosanoids as inflammatory mediators in the regulation of experimental Lyme arthritis. Eicosanoids, such as PGE2 and LTB4, are powerful regulators of inflammatory responses and thus may be important mediators of Lyme arthritis.
    Frontiers in Cellular and Infection Microbiology 05/2014; 4:69. DOI:10.3389/fcimb.2014.00069 · 3.72 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Worldwide the elderly population is increasing. The elderly show deficiencies in immune function. B lymphocytes are essential elements of the immune system responsible for antibody production. This laboratory previously showed that activated human B cells isolated from young adults express cyclooxygenase-2 (Cox-2) and that Cox-2 is essential for optimal antibody responses. Recent data suggests that Cox-2 expression decreases with age in mouse bone tissue. There is no information regarding Cox-2 expression in B cells from older human subjects. We investigated the expression and activity of Cox-2 in naïve and memory B cells from older people. We show that B cells from older subjects show similar Cox-2 protein expression and activity, antibody production and proliferation compared to younger people. However, we found that activated memory B cells from older people produce higher levels of IL-6 and IL-10 compared to young adults. Therefore, the dysregulated cytokine production could contribute to immune senescence in the elderly.
    Cellular Immunology 09/2010; 266(1):90-7. DOI:10.1016/j.cellimm.2010.09.002 · 1.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Within inflammatory environments, B cells encountering foreign or self-Ag can develop tertiary lymphoid tissue expressing activation-induced cytosine deaminase (AID). Recently, this DNA-modifying enzyme was detected in nonlymphoid cells within several inflamed tissues and strongly implicated in malignant transformation. This study examines whether a cyclooxygenase 2 (COX-2) pathway, often linked to inflammation, influences AID expression in activated B lymphocytes. In this paper, we report that dividing human B cells responding to surrogate C3d-coated Ag, IL-4, and BAFF express AID, as well as COX-2. A progressive increase in AID with each division was paralleled by a division-related increase in a COX-2-linked enzyme, microsomal PGE(2) synthase-1, and the PGE(2)R, EP2. Cells with the greatest expression of AID expressed the highest levels of EP2. Although COX-2 inhibitors diminished both AID expression and IgG class switching, exogenous PGE(2) and butaprost, a selective EP2 agonist, augmented AID mRNA/protein and increased the numbers of IgG(+) progeny. Despite the latter, the proportion of IgG(+) cells within viable progeny generally declined with PGE(2) supplementation. This was not due to PGE(2)-promoted differentiation to plasma cells or to greater downstream switching. Rather, because phosphorylated ataxia telangiectasia mutated levels were increased in progeny of PGE(2)-supplemented cultures, it appears more likely that PGE(2) facilitates AID-dependent DNA double-strand breaks that block B cell cycle progression or promote activation-induced cell death, or both. Taken together, the results suggest that a PGE(2) feed-forward mechanism for augmenting COX-2 pathway proteins promotes progressively increased levels of AID mRNA, protein, and function.
    The Journal of Immunology 10/2010; 185(9):5300-14. DOI:10.4049/jimmunol.1000574 · 4.92 Impact Factor
Show more