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Introduction: Proton beam radiotherapy is an advanced cancer treatment technique, which would reduce the effects of radiation on the surrounding healthy cells. The usage of radiosensitizers in this technique might further elevate the radiation dose towards the cancer cells. Material and methods: The present study investigated the production of intracellular reactive oxygen species (ROS) due to the presence of individual radiosensitizers, such as bismuth oxide nanoparticles (BiONPs), cisplatin (Cis) or baicalein-rich fraction (BRF) from Oroxylum indicum plant, as well as their combinations, such as BiONPs-Cis (BC), BiONPs-BRF (BB), or BiONPs-Cis-BRF (BCB), on HCT-116 colon cancer cells under proton beam radiotherapy. Results: It was found that the ROS in the presence of Cis at 3 Gy of radiation dose was the highest, followed by BC, BiONPs, BB, BRF, and BCB treatments. The properties of bismuth as a radical scavenger, as well as the BRF as a natural compound, might contribute to the lower intracellular ROS induction. The ROS in the presence of Cis and BC combination were also time-dependent and radiation dose-dependent. Conclusions: As the prospective alternatives to the Cis, the BC combination and individual BiONPs showed the capacities to be developed as radiosensitizers for proton beam therapy.

Baicalein was proved to have an apoptotic effect on a wide range of cancer cells in numerous studies. In this study, the apoptotic effect of baicalein-rich fraction from Oroxylum indicum leaves on human cervical cancer cells (SiHa and HeLa) were investigated. In this case, BRF-induced cell death was regulated by the activation of JNK/p38 and deactivation of ERK. Apart from that, BRF was able to trigger mitochondrial-mediated apoptosis pathway by downregulating Bcl-2 as well as upregulating Bax, caspase-9 and caspase-3. Indeed, MAPK transduction was found to be involved in BRF action in modulating mitochondrial Bcl-2 family, Bcl-2 and Bax. In SiHa cells, ERK and p38 pathway regulated BRF stimulation on mitochondrial-mediated pathway. Yet, BRF-induced this apoptosis pathway in ERK/JNK/p38-dependent manner in HeLa cells. Therefore, BRF induced and augmented the cell death of human cervical cancer cells through MAPK transduction.

Noor Nabilah Talik Sisin,1 Nor Fazila Che Mat,1 Raizulnasuha Ab Rashid,1 Norhayati Dollah,2 Khairunisak Abdul Razak,3 Moshi Geso,4 Merfat Algethami,5 Wan Nordiana Rahman1 1School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; 2Department of Nuclear Medicine, Radiotherapy and Oncology, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; 3School of Materials and Mineral Resources Engineering, Universiti Sains Malaysia, Nibong Tebal, Penang, Malaysia; 4School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia; 5Faculty of Science, Taif University, Al Hawiyah, Taif, Saudi ArabiaCorrespondence: Wan Nordiana Rahman, School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia, Tel +6097677811, Email wandiana@usm.myPurpose: Chemotherapy has been used in conjunction with radiation therapy to improve the treatment outcomes of cancers. Cisplatin (Cis) is a standard treatment that has been used as a chemotherapeutic drug in medical settings. However, the possibility of complications constrains the treatment due to the exposure of healthy organs to unnecessary radiation and the drugs’ toxicities. As a result, researchers have been looking for non-toxic chemotherapeutic agents which can be used as radiosensitizers, possibly produced from natural derivatives and nano sized materials.Methods: BRF, Cis, and BiONPs were irradiated individually and in combinations with 6 MV of photon beam and 6 MeV of electron beams with 0 to 10 Gy radiation doses on MCF-7, MDA-MB-231, and NIH/3T3 cell lines. Then, the experimental sensitization enhancement ratios (SER) of each treatment obtained were compared to the theoretical dose enhancement factor (DEF). The interactions within the BRF-BiONPs (BB) and BRF-Cis-BiONPs (BCB) combinations were also estimated using the Combination Index (CI).Results: BRF induced radiosensitization in all cells under 6 MV photon beam (SER of 1.06 to 1.35), and MDA-MB-231 cells only under 6 MeV electron beam (SER = 1.20). The highest SER values for BiONPs and Cis were obtained from MCF-7 cells under a 6 MeV electron beam (SER of 1.50 and 2.24, respectively). The theoretical DEFs were generally lower than the experimental SERs. Based on the SER and CI relationships, it was estimated that BB and BCB therapy methods interacted in either a synergistic or additive manner.Conclusion: The BRF is found to induce relatively less radiosensitization effects compared to the BiONPs and Cis. The BB and BCB combinations have shown better effects with potential for becoming competently suitable radiosensitizers in breast cancer therapies.Keywords: baicalein, bismuth oxide, nanoparticles, cisplatin, radiosensitization, synergism

A novel coronavirus disease (COVID-19) or severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), transmitted from person to person, has quickly emerged as the pandemic responsible for the current global health crisis. This infection has been declared a global pandemic, resulting in a concerning number of deaths as well as complications post-infection, primarily among vulnerable groups particularly older people and those with multiple comorbidities. In this article, we review the most recent research on the role of date palm (Phoenix dactylifera L.) fruits (DPFs) to prevent or treat COVID-19 infection. The mechanisms underlying this preventive or therapeutic effect are also discussed in terms of bioactivity potentials in date palm, e.g., antimicrobial, antioxidant, anticancer, anti-diabetic, anti-inflammatory, neuroprotective, and hemolytic potential, as well as prospect against COVID-19 disease and the potential product development. Therefore, it can be concluded that regular consumption of DPFs may be associated with a lower risk of some chronic diseases. Indeed, DPFs have been widely used in folk medicine since ancient times to treat a variety of health conditions, demonstrating the importance of DPFs as a nutraceutical and source of functional nourishment. This comprehensive review aims to summarize the majority of the research on DPFs in terms of nutrient content and biologically active components such as phenolic compounds, with an emphasis on their roles in improving overall health as well as the potential product development to ensure consumers' satisfaction in a current pandemic situation. In conclusion, DPFs can be given to COVID-19 patients as a safe and effective add-on medication or supplement in addition to routine treatments.

Purpose The aim of this study was to investigate the potential of the synergetic triple therapeutic combination encompassing bismuth oxide nanoparticles (BiONPs), cisplatin (Cis), and high dose rate (HDR) brachytherapy with Ir-192 source in breast cancer and normal fibroblast cell line. Methods In vitro models of breast cancer cell lines (MCF-7, MDA-MB-231) and normal fibroblast cell line (NIH/3T3) were employed. Cellular localization and cytotoxicity studies were conducted prior to inspection on the radiosensitization effects and generation of reactive oxygen species (ROS) on three proposed radiosensitizers: BiONPs, Cis, and BiONPs-Cis combination (BC). The optimal, non-cytotoxic concentration of BiONPs (0.5 mM) and the 25% inhibitory concentration of Cis (1.30 µM) were applied. The radiosensitization effects were evaluated by using a 0.38 MeV Iridium-192 HDR brachytherapy source over a prescribed dose range of 0 Gy to 4 Gy. Results The cellular localization of BiONPs was visualized by light microscopy and accumulation of the BiONPs within the vicinity of the nuclear membrane was observed. Quantification of the sensitization enhancement ratio extrapolated from the survival curves indicates radiosensitization effects for MCF-7 and MDA-MB-231 when treated with BiONPs, Cis, and BC. However, NIH/3T3 cells exhibited contradictive behavior as it only reacted towards the BC combination. Nonetheless, the MCF-7 cell line loaded with BC shows the highest SER of 4.29. ROS production analysis, on the other hand, shows that Cis and BC radiosensitizers generated the highest free radicals in comparison to BiONPs alone. Conclusion A BiONPs-Cis combination was unveiled as a novel approach that offers promising radiosensitization enhancement that will increase the efficiency of tumor control while preserving the normal tissue at a reduced dose. This data is the first precedent to prove the synergetic implication of BiONPs, Cis, and HDR brachytherapy that will be beneficial for future chemoradiotherapy strategies in cancer care.

Objective: To examine the proapoptotic properties of Oroxylum indicum methanol extract on cervical cancer cells. Methods: Methylene blue assay was used to determine the IC50 value of the extract. Western blotting assays were done to analyze the expression of HPV oncoproteins (HPV18 E6 and E7) and apoptotic molecules (caspase-3 and caspase-8). Reverse transcriptase PCR assays were performed to determine genetic alteration of tumor suppressors p53 and pRb and apoptosis markers Fas and FasL. Enzyme-linked immunosorbent assay (ELISA) was done to determine the expression of cytokine levels (IL-6 and IL-12). Results: The determination of IC50 value indicated a higher anti-proliferative activity of the extract compared to cisplatin. After 24 hours of treatment, Western blot analysis showed that treated HeLa cells exhibited a significant down-regulation of HPV18 oncoproteins E6 and E7, and a significant induction of caspase-8 and caspase-3 activation level. Meanwhile, the mRNA expressions of p53, pRb, Fas and FasL were significantly upregulated in treated cells. Moreover, ELISA showed an increased IL-12 and decreased IL-6 production after Oroxylum indicum treatment. Conclusions: The methanol extract of Oroxylum indicum has an anti-proliferative activity and proapoptotic potential. It induces localized-immunity improvements by altering cytokine production in HPV-positive cervical cancer cells.

Radiotherapy is an important treatment modality for cancer treatment, particularly for locally advanced tumours and it is known to induce cell death in tumours. Radiotherapy is limited by the total dose that can be prescribed without damaging normal tissueThe main aims of radiotherapy to optimally eradicate tumours while sparing the normal tissue could be achieved with the combination treatment using natural products based medicinal plants. Oroxylum indicum (OI) is a Malaysian consumable plant with a variety of health attributes that contains useful active biocompound that serves as anticancer agent. In this study, the potentials of OI extracts to increase cells radiosensitivity towards radiotherapy were investigated. Initially, the cytotoxic effects of OI extracts were determined in-vitro using HeLa cells. The cells with non-toxic concentration of OI extracts were irradiated with 6 MV and 10 MV photon beams. The cell survivals after irradiation were then evaluated using PrestoBlue assay. The OI extracts with maximum concentration of 0.01 mg/ml are found nontoxic to HeLa cells. The combination of OI extracts and irradiation are found to reduce the cells survival which indicates radiosensitization effects. The sensitization enhancement ratio (SER) calculated indicate higher radiosensization observed for 6 MV photon beams compare to 10 MV photon beams. SER also increased at higher OI concentration. In conclusion, the OI extracts are found to induce radiosensitization in HeLa cancer cells when irradiated with megavoltage photon beams. This study indicates the potential of plant based natural product to be applied as radiosensitizer to increase the therapeutic efficiency in radiation therapy of cancer.

Coronavirus disease 19 (COVID-19) can be transmitted via contact with affected individuals and social distancing is widely practiced as a public preventive measure to contain the disease. Social distancing implementation includes maintaining at least one-meter gap from other people, avoiding mass gatherings and staying out of crowded places. To ensure successful implementation of social distancing, many countries including Malaysia have opted for Movement Control Order (MCO). Under MCO, mass assembly of cultural, religious, and social events are prohibited, education institutions, government, and public premises are closed and strict restrictions to leave and enter the country. Here, we provide several clusters of COVID-19 cases in Malaysia that emerged due to non-conformity to social distancing. Our report is thus providing informed decision to policy makers for designing a better pandemic response plan in the country.

Noor Nabilah Talik Sisin,1 Khairunisak Abdul Razak,2 Safri Zainal Abidin,3 Nor Fazila Che Mat,1 Reduan Abdullah,1,4 Raizulnasuha Ab Rashid,1 Muhammad Afiq Khairil Anuar,1 Wan Nordiana Rahman1 1Medical Radiation Programme, School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan,Malaysia; 2Material Engineering Programme, School of Materials and Mineral Resources Engineering, Universiti Sains Malaysia, Nibong Tebal, Penang, Malaysia; 3Oncological and Radiological Sciences Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Penang, Malaysia; 4Nuclear Medicine, Radiotherapy and Oncology Department, Hospital of Universiti Sains Malaysia, Kubang Kerian, Kelantan, MalaysiaCorrespondence: Wan Nordiana RahmanSchool of Health Sciences, Universiti Sains Malaysia, Kelantan, MalaysiaTel +6097677811Email wandiana@usm.myPurpose: This study aimed to quantify synergetic effects induced by bismuth oxide nanoparticles (BiONPs), cisplatin (Cis) and baicalein-rich fraction (BRF) natural-based agent on the reactive oxygen species (ROS) generation and radiosensitization effects under irradiation of clinical radiotherapy beams of photon, electron and HDR-brachytherapy. The combined therapeutic responses of each compound and clinical radiotherapy beam were evaluated on breast cancer and normal fibroblast cell line.Methods: In this study, individual BiONPs, Cis, and BRF, as well as combinations of BiONPs-Cis (BC), BiONPs-BRF (BB) and BiONPs-Cis-BRF (BCB) were treated to the cells before irradiation using HDR brachytherapy with 0.38 MeV iridium-192 source, 6 MV photon beam and 6 MeV electron beam. The individual or synergetic effects from the application of the treatment components during the radiotherapy were elucidated by quantifying the ROS generation and radiosensitization effects on MCF-7 and MDA-MB-231 breast cancer cell lines as well as NIH/3T3 normal cell line.Results: The ROS generated in the presence of Cis stimulated the most substantial amount of ROS compared to the BiONPs and BRF. Meanwhile, the combination of the components had induced the higher ROS levels for photon beam than the brachytherapy and electron beam. The highest ROS enhancement relative to the control is attributable to the presence of BC combination in MDA-MB-231 cells, in comparison to the BB and BCB combinations. The radiosensitization effects which were quantified using the sensitization enhancement ratio (SER) indicate the highest value by BC in MCF-7 cells, followed by BCB and BB treatment. The radiosensitization effects are found to be more prominent for brachytherapy in comparison to photon and electron beam.Conclusion: The BiONPs, Cis and BRF are the potential radiosensitizers that could improve the efficiency of radiotherapy to eradicate the cancer cells. The combination of these potent radiosensitizers might produce multiple effects when applied in radiotherapy. The BC combination is found to have the highest SER, followed by the BCB combination. This study is also the first to investigate the effect of BRF in combination with BiONPs (BB) and BC (BCB) treatments.Keywords: cisplatin, bismuth oxide, baicalein, radiosensitization, reactive oxygen species

Malaysia has recorded the highest number of COVID-19 cases in Southeast Asia with more than 35% of new COVID-19 cases linked to the Sri Petaling gathering, a Moslem missionary movement attended by more than 19 000 people of different nationalities, in March 2020 in Kuala Lumpur. From this cluster, 1701 samples have been tested positive out of 21 920 tests carried out. Thus, mass gathering during COVID-19 pandemic period should be banned to curb disease transmission.

In this study, 268 samples for unrelated males belonging to the five major human subpopulation groups in Ghana (Akan, Ewe, Mole-Dagbon, Ga-Dangme and Guang) were genetically characterised for 23 Y chromosome short tandem repeat (STR) loci using the Powerplex® Y23 STR kit. A total of 263 complete haplotypes were recorded of which 258 were unique. The haplotype diversity, discriminating capacity and match probability for the pooled population data were 0.9998, 0.9627 and 0.0039, respectively. The pairwise genetic distance (RST) for the Ghanaian datasets and other reference populations deposited in the Y-STR Haplotype Reference Database (YHRD) were estimated and mapped using multidimensional scaling (MDS) plot. The Guang and Ewe were significantly different from the Akan, Mole-Dagbon and Ga-Dangme. However, the five Ghanaian datasets were all plotted close together with other African populations in the MDS data mapping.

Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus that poses a threat to human worldwide. Driven by the lack of approved medication and vaccination, research on anti-Chikungunya agents has received great attention. In an effort to determine potential inhibitor of CHIKV, this study aimed at investigating the potential anti-viral activity of Oroxylum indicum extracts towards CHIKV-infected Vero cells. The virucidal, pre- and post-treatment effects of O. indicum were evaluated, using the maximum non-toxic dose of O. indicum methanol and aqueous extracts as determined by cytotoxicity assay. The viral inhibitory effect was assessed by the morphological changes of Vero cells and further confirmed by plaque assay. Both methanol and aqueous extracts of O. indicum had similar cytotoxicity in Vero cells. Interestingly, the virucidal effect of O. indicum aqueous extract revealed a significant reduction on the viral titre (p

Dendritic cells produce IL-12 and IL-23 in response to viral and bacterial infection and these cytokines are responsible for successful pathogen clearance. How sequential viral and bacterial infections affect the production of IL-12 and IL-23 is currently not known. Our study demonstrates that in dendritic cells infected with Lymphocytic choriomeningitis virus (LCMV), TLR activation with bacterial PAMPs resulted in reduced IL-12 and IL-23 expression compared to non-infected cells. Furthermore, expression of other proinflammatory cytokines, TNF-α and IL-6, were not inhibited under these conditions. We discovered that TLR-induced phosphorylation of p38 was significantly inhibited in LCMV-infected cells. We detected enhanced expression of suppressor of cytokine signalling (SOCS)-3 and IL-10. Yet, neutralizing IL-10 did not restore IL-12/IL-23 expression. Taken together, these results show that virus infection interferes with the magnitude of TLR-mediated inflammatory responses by repressing specific cytokine expression.

Interleukin (IL)-23 plays a critical role in the development of the T helper (Th) cell response and is responsible for the maintenance of the IL-17 producing subset of Th cells, Th17. IL-23 is a heterodimeric cytokine composed of IL-23p19 and IL-12p40 subunits, and the signaling pathway for IL-23 involves 2 receptor chains: IL-12Rβ1 and IL-23Rα. The IL-23 receptor complex is expressed on a number of cells, including natural killer cells, monocytes, macrophages, dendritic cells, and CD4 T cells. Currently, the molecular mechanisms governing expression of the IL-23 receptor chains, IL-23Rα and IL-12Rβ1, are not well understood. Our results show that IL-23 induces upregulation of IL-23Rα and IL-12Rβ1 expression in human CD4 T cells. Further, we demonstrate that inhibition of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway by SD-1029, a JAK2 inhibitor, 5'-deoxy-5'-(methylthio) adenosine, a STAT1 inhibitor, and STAT3 VII, a STAT3 inhibitor, were able to block IL-23-induced expression of IL-23 receptor subunits in the human SUPT-1 T cell line and in primary CD4 human T cells. Taken together, our results suggest a positive feedback regulation of the IL-23 receptor via IL-23-mediated activation of the JAK/STAT pathway.

IL-27 is a heterodimeric cytokine bridging innate and adaptive immunity by playing a role in the activation of naive T cells and in development of Th1 cells. Additionally, recent evidence supports a role for IL-27 in the activation of monocytic cells. Both pro-inflammatory and anti-inflammatory activities have been attributed to IL-27; however, the role played by IL-27 in the activation of human monocytic cells in terms of cytokine production has not been well described. Our results show that IL-27 is a strong inducer of proinflammatory cytokine and chemokine expression, including enhancement of IL-6, IP-10, MIP-1alpha, MIP-1beta, and TNF-alpha expression in human primary monocytes. Furthermore, we observed that IL-27-induced cytokine and chemokine production was mediated by STAT1, STAT3, and NF-kappaB activation. Understanding how IL-27 exerts its effects on monocytic cells will identify important molecular mechanisms in the regulation of immune responses, particularly in the modulation of monocyte activation.

A newly described cytokine, interleukin-27 (IL-27), that activates naive CD4 T cells, has recently been shown to be an anti-HIV cytokine. However, the effect of HIV infection on IL-27 expression has not been characterized. We found that clinical characteristics, including HIV viral load, hepatitis C virus coinfection, and CD4 T cell counts, were associated with changes in serum IL-27. Overall, our results suggest circulating HIV may suppress IL-27, a critical concept in treatment development with this cytokine.

Transfusion procedures are always complicated by potential genetic mismatching between donor and recipient. Compatibility is determined by several major antigens, such as the ABO and Rhesus blood groups. Matching for other blood groups (Kell, Kidd, Duffy, and MNS), human platelet antigens, and human leukocyte antigens (HLAs) also contributes toward the successful transfusion outcomes, especially in multitransfused or highly immunized patients. All these antigens of tissue identity are highly polymorphic and thus present great challenges for finding suitable donors for transfusion patients. The ABO blood group and HLA markers are also the determinants of transplant compatibility, and mismatched antigens will cause graft rejection or graft-versus-host disease. Thus, a single and comprehensive registry covering all of the significant transfusion and transplantation antigens is expected to become an important tool in providing an efficient service capable of delivering safe blood and quickly locating matching organs/stem cells. This review article is intended as an accessible guide for physicians who care for transfusion-dependent patients. In particular, it serves to introduce the new molecular screening methods together with the biology of these systems, which underlies the tests.

Cytokines are involved in immune responses and the pathogenesis of various diseases. Allelic variations within the genes coding for various ∼30 kDa cytokine protein/glycoproteins have been reported for many populations and have been the subjects of many ancestry and health analyses. In this study, we typed 22 single nucleotide polymorphisms (SNPs) in 13 cytokine genes of 165 Orang Asli individuals by using sequence specific primer-polymerase chain reaction (SSP-PCR) assay. The volunteers came from all across the Peninsular of Malaysia and belong to six Orang Asli subgroups; Batek, Kensiu, Lanoh, Che Wong, Semai and Orang Kanaq. Here we report our general findings and original genotype data and their associated analyses (Hardy-Weinberg proportions, estimation of allele and haplotype frequencies) can be found in the supplementary files and will be held at Allele Frequency Net Database (AFND).

OBJECTIVE: To characterize the effect of HIV infection on IL-27-induced gene expression. DESIGN: During HIV infection, cytokine expression and function become deregulated. IL-27 is an important modulator of inflammatory responses. Interestingly, IL-27 can inhibit HIV replication in T cells and monocytes, implicating IL-27 as a potential adjunct to anti-viral treatment. Our previous work demonstrated that circulating HIV may suppress IL-27 expression, therefore, this study, in continuation of our previous work, aimed to understand how HIV affects expression levels of the IL-27 receptor and downstream functions of IL-27. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from whole blood of HIV negative and HIV positive (viremic) individuals to assess IL-27-induced gene expression by flow cytometry and ELISA. PBMC were also processed for monocyte enrichment to assess IL-27 receptor expression by flow cytometry and real-time PCR. RESULTS: Expression of the IL-27 receptor subunit, gp130, was upregulated in response to IL-27 in HIV negative individuals, however, in HIV positive individuals, this IL-27 response was diminished. Furthermore, we observed downregulation of IL-27-induced IL-6, TNF-α, and IL-10 expression in HIV positive subjects. CONCLUSION: In HIV infection, IL-27-induced gene expression was impaired, indicating HIV-mediated dysregulation of IL-27 functions occurs during HIV infection. This study provides evidence for new viral pathogenic mechanisms contributing to the widespread impairment of immune responses observed in HIV pathogenesis.

1.1 Th cell development Regulation of T helper (Th) cell differentiation and proliferation depends on which cytokines are present in the microenvironment of a naive Th cell. Induction of specific transcription factors results in programming of the naive Th0 cell into one of several subsets. Currently there are four well characterized Th cell subsets, namely Th1, Th2, Th17, and the T regulatory (Treg) cells (Figure 1). In this chapter we will be focusing on the Th1, Th17, and Treg cell populations. However, at this point it is also worth mentioning the relatively newly described Th9 and follicular (Tfh) cell subsets. Here we briefly discuss the differentiation pathways taken by a Th0 cell that ultimately results in the formation of these different subsets. Since the early 1980’s, the Th1/Th2 paradigm has been well-studied. Th1 cells are known for expression of the signature cytokine IFN-┛ and resulting anti-viral activities. The necessary driving cytokine for these cells is IL-12 in conjunction with the Th1-specific transcription factor T-bet (Hsieh, Macatonia et al., 1993; Seder, Gazzinelli et al., 1993;Szabo, Sullivan et al., 2002). IL-27, related to IL-12, has been recently shown to play a role in the induction of Th1 cells, while also actively repressing development of other subsets. On the other hand, Th2 cells are largely recognized to support humoral immunity and are induced by the presence of IL-4 and resulting activation of the STAT6 transcription factor(Kaplan, Schindler et al., 1996;Kurata, Lee et al., 1999). Equally important is the activation of the GATA binding protein 3 (GATA-3), the main regular of Th2 development (Pai, Truitt et al., 2004;Zhu, Min et al., 2004). The newly defined Th17 cells have been implicated in a number of inflammatory disorders and are recognized as key Th cells that trigger massive proinflammatory responses. They are characterized by production of IL-17 and differentiation of these cells requires both tumor growth factor (TGF)-β and IL-6 which act together to promote development of the Th17 subset (Bettelli, Carrier et al., 2006; Mangan, Harrington et al., 2006). Additionally important to the generation of these cells is IL-23, which functions to aid in the development and proliferation of Th17 cells. The key transcription factors required belong to the retinoic acid-related orphan receptors (ROR)

Cytokines are critical coordinators of the immune response necessary for resolving bacterial and viral assaults on the immune system. In particular, the IL-12 family of cytokines are key players in the regulation of T cell responses. These responses are orchestrated by monocytes, macrophages, and dendritic cells which produce the members of the IL-12 family of cytokines in response to infection. IL-27 and IL-23 are two cytokines that are related to IL-12; these cytokines share homology at the subunit, receptor, and signalling levels. IL-12 is composed of p35 and p40 subunits, which, when combined together form the bioactive IL-12p70. IL-23 is composed of the IL-12p40 subunit as well as the IL-23p19 subunit, which shares homology with IL-12p35. IL-27 is composed of EBI3 and p28. These three cytokines activate similar members of the JAK/STAT signalling pathways as a result of homology in their receptor components. Production of these cytokines by activated monocytes, macrophages, and dendritic cells results in the activation and differentiation of T cells. In spite of their similarity, each of these cytokines has specific roles in the regulation of immune responses. IL-12 is required for the induction of IFN-gamma production, critical for the induction of Th1 cells. IL-27 has been shown to play a role in the induction of Th1 cells from naive T cells, whereas IL-23 has been demonstrated to play a key role in the induction of the newly described Th17 cells. Recently, a novel heterodimeric and anti-inflammatory cytokine composed of the IL-12p35 and EBI3 subunits has been identified as IL-35. The biological properties of the IL-12 family of cytokines, the signalling pathways mediated by these cytokines and their role in infection, inflammation, and autoimmune diseases will be the focus of this review.