It was generally believed that the mammalian heart is a post-mitotic organ and therefore lacks the ability to regenerate or self-renew. However, this notion has been challenged by recent studies suggesting that the adult heart has the capability to create new muscle cells and that there exist cardiac stem/progenitor cells with the potential to differentiate into multiple cell types in the heart. It is also known that lower vertebrates such as amphibians or fish readily regenerate the injured heart. Elucidation of the molecular and cellular mechanisms of heart regeneration will eventually lead to the novel therapeutic approaches to enhance the regenerative capacity of the diseased human heart.

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Rheumatoid arthritis (RA) is a representative inflammatory disease characterized with systemic, chronic and destructive synovitis and subsequent bone destruction that causes severe disability and mortality. Since joint destruction occurs from the early disease, its diagnosis and treatment have to be done timely. The combinational use of methotrexate and biologics targeting TNF and IL-6 has revolutionized the treatment of RA, producing significant improvements in clinical and structural outcomes. On the other hand, an anti-RANKL antibody denosumab possesses a potential to inhibit joint destruction and peri-articular osteoporosis as well as systemic and glucocorticoid-mediated osteoporosis. Thus, differential efficacy of different therapies in bone destruction and osteoporosis would warrant further study to clarify the mechanisms of bone and joints diseases.

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Treatment of rheumatoid arthritis (RA) with biologic agents targeting inflammatory cytokines and cell surface molecules such as tumor necrosis factor and Interleukin-6 is generally more efficacious than traditional disease-modifying antirheumatic drugs when combined with MTX. However, not only do ∼30% of patients poorly respond to treatment but also parenteral mode of administration and expense are issues to be solved. Recently, a kinase inhibitor targeting Janus kinases (JAKs), has shown high efficacy in active RA in clinical trials. Among several JAK inhibitors in clinical trials for RA, tofacitinib is a step ahead for use in clinical practice. Kinase inhibitors are orally available, which is a major advantage over biologic agents, in addition to being less expensive. This review describes recent advance in JAK inhibitors for RA and its possible mechanism of action.

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Bone destruction associated with rheumatoid arthritis (RA) is caused by the enhanced activation of osteoclasts, which are terminally differentiated cells of monocyte/macrophage lineage that resorb bone matrix. Accumulating evidence lends support to the theory that interleukin (IL)-17-producing helper T (Th17) cells induce the expression of receptor activator of nuclear factor-κB ligand (RANKL) in synovial cells, which in turn stimulates the differentiation and activation of osteoclasts together with inflammatory cytokines. Thus, a better understanding of the mechanism of Th17 induction is important for the development of effective therapeutic strategies against RA. Our study indicates that cathepsin K, which was thought to be an osteoclast-specific enzyme, also functions as a regulator of TLR9 signaling in dendritic cells, and thus is a potential therapeutic target for the control of Th17-mediated autoimmune inflammation. Furthermore, we have explored the transcriptional program of Th17 development, and discovered that the transcriptional regulator IκBξ is essential for the development of Th17 cells. These findings comprise an important advance in our understanding of the mechanism of Th17 development, providing molecular basis for novel effective therapeutic approaches.

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Cell reprogramming technology opens a new insight in not only basic biology but also clinical medicine including immune cell therapy. Application of cell reprogramming technique in manipulating immune cells may bring beneficial results in tumor immunotherapy. In this manuscript, current status of the cell reprogramming in immune cells especially lymphocytes is summarized, and its perspective is discussed.

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Cytokines and chemokines induce the migration, activation, proliferation, and/or differentiation of inflammatory cells and resident cells, and participate in the pathogenesis of some autoimmune diseases. Some of these molecules are effective therapeutic targets. Anti-tumor necrosis factor (TNF)-α and anti-interleukin (IL)-6 therapies are effective in patients with rheumatoid arthritis, and have markedly altered the therapeutic strategies for this disease. In ischemic kidney disease, cytokines and chemokines also play key roles in the progression of tissue destruction or remodeling. Accumulated data regarding ischemic kidney disease suggested that chemokines or chemokine receptors participate in unique pathological changes at particular time points in renal injury. Some molecules involved in these cytokine/chemokine cascades are potential therapeutic targets. In addition to antagonists for single chemokine receptors, promiscuous antagonists for chemokine receptors are currently under investigation. Further studies are needed to develop cytokine- and chemokine-based therapeutic strategies for ischemic kidney injury.

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Phospholipase Cε (PLCε), encoded by PLCE1, is the phosphoinositide-specific PLC regulated by the ras proto-oncogene product Ras and its relative Rap1. Like other PLC isoforms, PLCε catalyzes hydrolysis of phosphatidylinositol 4,5-bisphosphate to yield second messengers, diacylglycerol and inositol 1,4,5-trisphosphate. To understand the physiological function of PLCε, we have created and analyzed genetically-modified mice in which PLCε is inactivated or overproduced. PLCε knockout (KO) mice are resistant to two-stage skin chemical carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and to intestinal tumorigenesis caused by the loss-of-function mutation of the APC tumor suppressor gene. In PLCε KO mice, inflammation, such as that induced by a single application of PMA, that associated with tumorigenesis, and that in the elicitation phase of allergic contact hypersensitivity, is also attenuated as compared to that in wild-type mice. Conversely, overexpression of PLCε in the epidermis results in the development of skin inflammation that partly shares the features with human psoriasis. In this article, we summarize the data showing the role of PLCε in tumorigenesis and inflammation and discuss the future directions of the study of PLCε for the development of therapies to control inflammation and to prevent cancer progression.

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Endothelial cells function as a barrier between the intravascular compartment and extravascular tissues. At the site of inflammation, endothelial cells are impaired through the apoptosis, and vascular integrity is disrupted. Thus, apoptosis of endothelial cells triggers the microcirculatory disorder and organ dysfunction, and its attenuation is considered to be one of the therapeutic strategies for inflammatory diseases, including sepsis. Cathelicidins are the family of antimicrobial peptides found in several mammalian species. They are constitutively expressed by neutrophils and epithelial cells in normal condition, and abundantly induced upon infectious or inflammatory stimuli. In addition to the broad spectrum of bactericidal activities, cathelicidins diversely affect biological functions such as chemotaxis and cytokine production, thereby modulating inflammatory or immune responses. Moreover, some cathelicidins exhibit angiogenic activity against ischemic endothelial cells, suggesting their therapeutic role for vascular damage. Consistently, two cathelicidins (porcine PR-39 and human LL-37) are reported to inhibit the apoptosis of endothelial cells. In this review, we introduce the effects of cathelicidins on the apoptosis of endothelial cells.

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