Increased inflammation and impaired resistance to Chlamydophila pneumoniae infection in Dusp1-/- mice: critical role of IL-6

Abstract

The MAPK phosphatase DUSP1 is an essential negative regulator of TLR-triggered innate immune activation. Here, we have investigated the impact of DUSP1 on inflammatory and antimicrobial host responses to the intracellular pathogen Chlamydophila pneumoniae. Following nasal infection, DUSP1-deficient mice mounted an enhanced pulmonary cytokine (IL-1beta, IL-6) and chemokine response (CCL3, CCL4, CXCL1, CXCL2), leading to increased leukocyte infiltration. Of interest, the increased inflammatory response, in the absence of DUSP1, was associated with higher bacterial numbers in the lungs, although the expression of IFN-gamma and critical antichlamydial effector molecules, such as iNOS, was intact. Blockade of IL-6 trans-signaling by injection of a soluble gp130-Fc fusion protein corrected the overshooting chemokine production as well as the increased chlamydial load in Dusp1(-/-) mice. Furthermore, IL-6 enhanced the replication of C. pneumoniae in embryonic fibroblasts in vitro. These data show that DUSP1 is required to achieve a balanced response to chlamydial infection and identify IL-6 as critical for amplifying inflammation and benefiting chlamydial growth through direct effects on infected cells.

EGR-1 and DUSP-1 are important negative regulators of pro-allergic responses in airway epithelium

“…EGR-1 and DUSP-1 can also be up-regulated by a variety of other stimuli representing both internal and external cell stress factors that may include pathogens/microorganisms, temperature, hypoxia, oxidative stress, or inflammatory mediators (Parra et al, 2011;Hammer et al, 2006). Deregulated expression of EGR-1 and DUSP-1 has also been linked to allergy-associated processes, such as cell adhesion (Liu et al, 1999), cell/tissue repair (Guerquin et al, 2013), wound healing (Braddock, 2001), control of protease inhibitors expression (Bae et al, 2002), immune modulation (Caceres et al, 2013), and cell recruitment (Rodriguez et al, 2010). Consequently, it does not come as a surprise that these transcription factors may also play a role in an allergic setting.…”

Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model*

“…To our knowledge, there are no data indicating that trans-signaling inhibition by sgp130Fc could interfere with the effect of antibiotics. In fact, recent studies reported that sgp130Fc abrogated the detrimental effect of dual specificity phosphatase-1 deficiency in mice infected with Chlamydophila pneumoniae (47) and protected mice from lipopolysaccharide-induced hypersensitivity and death (48).…”

Heat shock protein 10 of Chlamydophila pneumoniae induces proinflammatory cytokines through Toll-like receptor (TLR) 2 and TLR4 in human monocytes THP-1

“…Clinical studies reported the presence of C. pneumoniae and the antibodies against it in human serum (Davidson et al 1998;Kuo et al 1993;Kuo and Campbell 2000). Proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 can be secreted after C. pneumoniae infection (Tiran et al 2002;Yang et al 2003;Rodriguez et al 2010). Since inflammatory reactions may be involved in the development and progression of atherosclerosis, the components of C. pneumoniae which activate the host cells and initiate proinflammatory cytokines needs to be defined.…”