The Roles of Chemokines in Immune Response to Mycobacterial Infection

Tuberculosis (TB), a global and deadly infectious disease caused by Mycobacterium tuberculosis (Mtb), is manifested with host immune reaction. The balanced regulation between protective immune and pathologic inflammatory responses is critical to control progression to TB. Chemokines are a large family of cytokines that play an essential role for chemotaxis of immune and inflammatory cells to the sites of infection. Numerous chemokines including CXCL10 were reported as potential biomarkers of various stages of TB infection. In addition, several chemokines and their receptors play as key players to coordinate host immune defense as innate effectors and mediators of adaptive immune responses.Accumulating evidence suggests that some chemokines, if uncontrolled, are associated with host pathological inflammation during infection. In this review, we will discuss recent advances in understanding which chemokines have potentials as diagnostic markers. In addition, we focus the roles and mechanisms by which chemokines and their receptors are involved in both host immune protection and pathology during TB infection. The controlled activation of chemokine system will determine the coordinated biological outcomes of innate immune responses during pathogenic infection.

The Roles of Chemokines in Immune Response to Mycobacterial Infection

Tuberculosis (TB), a global and deadly infectious disease caused by Mycobacterium tuberculosis (Mtb), is manifested with host immune reaction. The balanced regulation between protective immune and pathologic inflammatory responses is critical to control progression to TB. Chemokines are a large family of cytokines that play an essential role for chemotaxis of immune and inflammatory cells to the sites of infection. Numerous chemokines including CXCL10 were reported as potential biomarkers of various stages of TB infection. In addition, several chemokines and their receptors play as key players to coordinate host immune defense as innate effectors and mediators of adaptive immune responses.Accumulating evidence suggests that some chemokines, if uncontrolled, are associated with host pathological inflammation during infection. In this review, we will discuss recent advances in understanding which chemokines have potentials as diagnostic markers. In addition, we focus the roles and mechanisms by which chemokines and their receptors are involved in both host immune protection and pathology during TB infection. The controlled activation of chemokine system will determine the coordinated biological outcomes of innate immune responses during pathogenic infection.

The Effects of Staphylococci on the Degranulation of Human Mast Cell-1

Atopic dermatitis (AD) is characterized by disturbances in epidermal barrier functions and the hyperactive immune response. Staphylococcus aureus (S. aureus) can be cultured from 90% of AD skin lesions and can exacerbate or contribute to the persistent skin inflammation in AD by secreting toxins with superantigenic properties. Superantigens can induce mast cell (MC) degranulation after penetrating the epidermal barrier. The role of MCs in AD is suggested by the increase in the MC number and MC activation. MCs are activated for degranulation and mediator release by allergens that cross-link IgE molecules or by microbial products. Therefore, MCs may be critically involved in the pathogenesis of AD. However, the understanding mechanisms of MC degranulation by S. aureus in relation to AD have still not been fully elucidated. In this study, we found that live S. aureus or methicillin-resistant S. aureus (MRSA) but not heat-killed bacteria induced MC degranulation. The heat-treatment partially inhibited MC degranulation by conditioned media (CM) of S. aureus or MRSA. The calcium chelator ethylene glycol tetraacetic acid (EGTA) did not block MC degranulation induced by live S. aureus or MRSA, but EGTA-treatment partially inhibited MC degranulation by CM from S. aureus or MRSA. These results suggest that live S. aureus and MRSA can degranulate MCs via direct interaction which may be important role in AD.

The Effects of Staphylococci on the Degranulation of Human Mast Cell-1

Atopic dermatitis (AD) is characterized by disturbances in epidermal barrier functions and the hyperactive immune response. Staphylococcus aureus (S. aureus) can be cultured from 90% of AD skin lesions and can exacerbate or contribute to the persistent skin inflammation in AD by secreting toxins with superantigenic properties. Superantigens can induce mast cell (MC) degranulation after penetrating the epidermal barrier. The role of MCs in AD is suggested by the increase in the MC number and MC activation. MCs are activated for degranulation and mediator release by allergens that cross-link IgE molecules or by microbial products. Therefore, MCs may be critically involved in the pathogenesis of AD. However, the understanding mechanisms of MC degranulation by S. aureus in relation to AD have still not been fully elucidated. In this study, we found that live S. aureus or methicillin-resistant S. aureus (MRSA) but not heat-killed bacteria induced MC degranulation. The heat-treatment partially inhibited MC degranulation by conditioned media (CM) of S. aureus or MRSA. The calcium chelator ethylene glycol tetraacetic acid (EGTA) did not block MC degranulation induced by live S. aureus or MRSA, but EGTA-treatment partially inhibited MC degranulation by CM from S. aureus or MRSA. These results suggest that live S. aureus and MRSA can degranulate MCs via direct interaction which may be important role in AD.

Bacillus spp. or Bacillus spp.-Derived Membrane Vesicles Induce the Intrinsic Pathways of Apoptosis of Human Colon Cancer Cell Lines

The striking increase in colorectal cancer (CRC) has shown the great fatality in Korea for more than 15 years. The leading edge of this rising incidence rate is mainly due to the people's dietary changes in Korea. Some studies have reported that the dietary fiber does not have significant cytotoxic effects on CRC cells, which contrasts to the effects of probiotics. It gives a positive evaluation that the nonpathogenic spore-forming Bacillus species among the probiotics including fermented bacteria might have optimistic effects on CRC incidence rate. Recently, we isolated Bacillus lentus (BL) from Korean soybean fermented food. BL showed the cytotoxic effect on human colon carcinoma cell lines HCT116 and SW480. Interestingly, BL did not have effect on human dermal fibroblast cells and human hepatoma cell line HepG2. It suggested that BL has the target cell-specific cytotoxicity toward human colon carcinoma cells. To clarify the death signaling pathway underlying the BL-induced apoptosis in cancer cells, we analyzed the expression of caspases, Bax and Bcl-2 by western blotting. The apoptotic effects by cytotoxic elements were executed by direct BL contact or membrane-derived vesicles isolated from BL. Treatment of HCT116 with BL activated caspase-9, -3 and increased cleavage form of poly (ADP-ribose) polymerase (PARP). However, caspase-8 activity was not increased by BL. BL-activated intrinsic pathway increased the pro-apoptotic Bax, decreased the anti-apoptotic Bcl-2 proteins on mitochondria, disrupted the mitochondrial membrane potential, and then released the cytochrome c from mitochondria. The membrane-derived vesicles (MVs) from BL induced apoptosis of the HCT116. Here, we propose that BL as a strong candidate for the development of apoptosis-specific anti-tumor agent will give great contribution to the understandings of the tumor-microbe interdisciplinary areas.

Characterization of Proinflammatory Responses and Innate Signaling Activation in Macrophages Infected with Mycobacterium scrofulaceum

Mycobacterium scrofulaceum is an environmental and slow-growing atypical mycobacterium. Emerging evidence suggests that M. scrofulaceum infection is associated with cervical lymphadenitis in children and pulmonary or systemic infections in immunocompromised adults. However, the nature of host innate immune responses to M. scrofulaceum remains unclear. In this study, we examined the innate immune responses in murine bone marrow-derived macrophages (BMDMs) infected with different M. scrofulaceum strains including ATCC type strains and two clinically isolated strains (rough and smooth types). All three strains resulted in the production of proinflammatory cytokines in BMDMs mediated through toll-like receptor-2 and the adaptor MyD88. Activation of MAPKs (extracellular signal-regulated kinase 1/2, and p38, and c-Jun N-terminal kinase) and nuclear receptor (NF)-kappaB together with intracellular reactive oxygen species generation were required for the expression of proinflammatory cytokines in BMDMs. In addition, the rough morphotypes of M. scrofulaceum clinical strains induced higher levels of proinflammatory cytokines, MAPK and NF-kappaB activation, and ROS production than other strains. When mice were infected with different M. scrofulaceum strains, those infected with the rough strain showed the greatest hepatosplenomegaly, granulomatous lesions, and immune cell infiltration in the lungs. Notably, the bacterial load was higher in mice infected with rough colonies than in mice infected with ATCC or smooth strains. Collectively, these data indicate that rough M. scrofulaceum induces higher inflammatory responses and virulence than ATCC or smooth strains.