Activin A: its role and involvement in inflammatory diseases

Activin proteins are members of the transforming growth factor-β family. Activin A is involved in several biological responses including wound repair, cell death, proliferation and differentiation of many cell types. Biologically active activins consist of homodimers or heterodimers of two beta (β) subunits that are linked together by a single covalent disulphide bond. The subunits in humans are βA, βB, βC and βE. As an example, a combination of two βA subunits will produce a unit of activin A. These proteins are found in most cells of body such as macrophage and activated circulating monocytes. Their role in inflammation can be categorised into two types, either pro- or anti-inflammatory agents, depending on the cell type and phase. Activin signals are kept in balance by antagonist follistatin (Fst), which is a glycoprotein expressed in tissues and encoded by the follistatin gene in humans

Receptor for advanced glycation end products and its involvement in inflammatory diseases

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily, capable of binding a broad repertoire of ligands. RAGE-ligands interaction induces a series of signal transduction cascades and lead to the activation of transcription factor NF- B as well as increased expression of cytokines, chemokines, and adhesion molecules. These effects endow RAGE with the role in the signal transduction from pathogen substrates to cell activation during the onset and perpetuation of inflammation. RAGE signaling and downstream pathways have been implicated in a wide spectrum of inflammatory-related pathologic conditions such as arteriosclerosis, Alzheimer's disease, arthritis, acute respiratory failure, and sepsis. Despite the significant progress in other RAGE studies, the functional importance of the receptor in clinical situations and inflammatory diseases still remains to be fully realized. In this review, we will summarize current understandings and lines of evidence on the molecular mechanisms through which RAGE signaling contributes to the pathogenesis of the aforementioned inflammation-associated conditions

Interleukin-27 exhibited anti-inflammatory activity during Plasmodium berghei infection in mice

Interleukin-27 (IL-27) has a pleiotropic role either as a pro-inflammatory or anti-inflammatory cytokine in inflammatory related diseases. The role and involvement of IL-27 during malaria was investigated and the effects of modulating its release on the production of major inflammatory cytokines and the histopathological consequences in major affected organs during the infection were evaluated. Results showed that IL-27 concentration was significantly elevated throughout the infection but no positive correlation with the parasitaemia development observed. Augmentation of IL-27 significantly elevated the release of anti-inflammatory cytokine, IL-10 whereas antagonising and neutralising IL-27 produced the opposite. A significant elevation of pro-inflammatory cytokines (IFN-γ and IL-6) was also observed, both during augmentation and inhibition of IL-27. Thus, it is suggested that IL-27 exerts an anti-inflammatory activity in the Th1 type response by signalling the production of IL-10 during malaria. Histopathological examination showed sequestration of PRBC in the microvasculature of major organs in malarial mice. Other significant histopathological changes include hyperplasia and hypertrophy of the Kupffer cells in the liver, hyaline membrane formation in lung tissue, enlargement of the white and red pulp followed by the disappearance of germinal centre of the spleen, and tubular vacuolation of the kidney tissues. In conclusion, it is suggested that IL-27 may possibly acts as an anti-inflammatory cytokine during the infection. Modulation of its release produced a positive impact on inflammatory cytokine production during the infection, suggesting its potential in malaria immunotherapy, in which the host may benefit from its inhibition

Modulation of receptor for advanced glycation end products signal transduction pathway as therapeutic option for malaria therapy

Receptor for advanced glycation endproducts (RAGE), an important receptor in the regulation of innate immune response, has been associated with many inflammatory related diseases such as septicaemia, rheumatoid arthritis, and arteriosclerosis. Malaria is also considered as an inflammatory disease involving excessive inflammatory response towards parasite invasion and severe systemic inflammation occurred during the infection has been closely linked to morbidity and mortality of the disease. However, RAGE involvement during malaria infection has yet to be revealed. In this study, the role and involvement of RAGE during malaria infection was investigated and the effects of modulating RAGE on the course of the infection, the release of major inflammatory cytokines and the histopathological consequences in major affected organs during malaria were evaluated. Plasmodium berghei (P. berghei) ANKA infection in male ICR mice was used as a model for malaria infection. The mice were inoculated intraperitoneally with 2 x 107 parasite-infected red blood cells (PRBCs) whereas the control mice received an equivalent dilution of normal RBCs. The plasma levels of RAGE in malarial mice were measured by ELISA. Results showed that RAGE was upregulated during malaria especially at the late critical phase of infection and there is a positive correlation between RAGE concentration and parasitaemia development suggesting that RAGE could be one of the important factors in mediating the severity of the infection. Modulation of RAGE expression was carried out by treatment of malarial mice with recombinant mouse RAGE Fc chimera (rmRAGE/Fc Chimera) or mouse RAGE polyclonal antibody (mRAGE/pAb) intravenously. Both treatments did not affect the parasitaemia development during malaria infection. Blocking RAGE signaling pathway during the infection period significantly result in an elevation in the plasma levels of interleukin (IL)-4 and IL-17A, a further increase in IL-10 and IL-2 plasma levels, and reduced secretion of interferon (IFN)-γ in the plasma. But no effect on the release of tumor necrosis factor (TNF)-α and IL-6 was observed. Histopathological examination was performed on five major organs affected during malaria including liver, spleen,brain, kidney, and lung. The results showed that modulation of RAGE expression improve the histopathological conditions of malaria to some degree. Both treatment groups showed an overall better outcome in histopathological conditions of all five organs despite the lack of effect on the course of the parasitaemia. In conclusion, the findings from this study showed that RAGE is involved during immune response towards malaria infection and blocking of RAGE may prove beneficial by reducing tissue injury to a lesser degree. Hence, this suggests the potential of RAGE as an immunotherapeutic target in malaria, in which the host may benefit from its inhibition

Review Article Receptor for Advanced Glycation End Products and Its Involvement in Inflammatory Diseases

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily, capable of binding a broad repertoire of ligands. RAGE-ligands interaction induces a series of signal transduction cascades and lead to the activation of transcription factor NF-B as well as increased expression of cytokines, chemokines, and adhesion molecules. These effects endow RAGE with the role in the signal transduction from pathogen substrates to cell activation during the onset and perpetuation of inflammation. RAGE signaling and downstream pathways have been implicated in a wide spectrum of inflammatory-related pathologic conditions such as arteriosclerosis, Alzheimer's disease, arthritis, acute respiratory failure, and sepsis. Despite the significant progress in other RAGE studies, the functional importance of the receptor in clinical situations and inflammatory diseases still remains to be fully realized. In this review, we will summarize current understandings and lines of evidence on the molecular mechanisms through which RAGE signaling contributes to the pathogenesis of the aforementioned inflammation-associated conditions

RAGE modulatory effects on cytokines network and histopathological conditions in malarial mice

This study was aimed at investigating the involvement of Receptor for Advanced Glycation End Products (RAGE) during malaria infection and the effects of modulating RAGE on the inflammatory cytokines release and histopathological conditions of affected organs in malarial animal model. Plasmodium berghei (P. berghei) ANKA-infected ICR mice were treated with mRAGE/pAb and rmRAGE/Fc Chimera drugs from day 1 to day 4 post infection. Survival and parasitaemia levels were monitored daily. On day 5 post infection, mice were sacrificed, blood were drawn for cytokines analysis and major organs including kidney, spleen, liver, brain and lungs were extracted for histopathological analysis. RAGE levels were increased systemically during malaria infection. Positive correlation between RAGE plasma concentration and parasitaemia development was observed. Treatment with RAGE related drugs did not improve survival of malaria-infected mice. However, significant reduction on the parasitaemia levels were recorded. On the other hand, inhibition and neutralization of RAGE production during the infection significantly increased the plasma levels of interleukin (IL-4, IL-17A, IL-10 and IL-2) and reduced interferon (IFN)-γ secretion. Histopathological analysis revealed that all treated malarial mice showed a better outcome in histological assessment of affected organs (brain, liver, spleen, lungs and kidney). RAGE is involved in malaria pathogenesis and targeting RAGE could be beneficial in malaria infected host in which RAGE inhibition or neutralization increased the release of anti-inflammatory cytokines (IL-10 and IL-4) and reduce pro-inflammatory cytokine (IFNγ) which may help alleviate tissue injury and improve histopathological conditions of affected organs during the infection