Src kinase (Src) is a tyrosine protein kinase that regulates cellular metabolism, survival, and proliferation. Many studies have shown that Src plays multiple roles in macrophage-mediated innate immunity, such as phagocytosis, the production of inflammatory cytokines/mediators, and the induction of cellular migration, which strongly implies that Src plays a pivotal role in the functional activation of macrophages. Macrophages are involved in a variety of immune responses and in inflammatory diseases including rheumatoid arthritis, atherosclerosis, diabetes, obesity, cancer, and osteoporosis. Previous studies have suggested roles for Src in macrophage-mediated inflammatory responses; however, recently, new functions for Src have been reported, implying that Src functions in macrophage-mediated inflammatory responses that have not been described. In this paper, we discuss recent studies regarding a number of these newly defined functions of Src in macrophage-mediated inflammatory responses. Moreover, we discuss the feasibility of Src as a target for the development of new pharmaceutical drugs to treat macrophage-mediated inflammatory diseases. We provide insights into recent reports regarding new functions for Src that are related to macrophage-related inflammatory responses and the development of novel Src inhibitors with strong immunosuppressive and anti-inflammatory properties, which could be applied to various macrophage-mediated inflammatory diseases.

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The Role of Src Kinase in Macrophage-Mediated Inflammatory Responses

As a chronic inflammatory disease of the liver, the pathogenic mechanisms of autoimmune hepatitis (AIH) have not yet been elucidated, with prognosis and diagnosis remaining unsatisfied. Currently the only viable treatments of AIH are immunosuppressant application and liver transplantation. It is considered that lack of good animal AIH models is the main reason for the shortage of a simple and efficient cure. The Concanavalin A (Con A) model is a typical and well established model for investigating T-cell and macrophage dependent liver injury in mice, which closely mimics the pathogenesis mechanisms and pathological changes of patients, and is regarded as the best experimental model for AIH research so far. In this paper we elucidated the pathogenic mechanisms of AIH and the evolution of relative animal models. We go on to further focus on Con A-induced liver injury from the point of immunological mechanisms and the change of cytokine levels. Finally, we manifested the clinical significance of the AIH animal models and the challenges they would meet during their future development.

Immune mechanisms of Concanavalin A model of autoimmune hepatitis

Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation

https://www.journal-of-hepatology.eu/article/S0168-8278(02)00417-8/pdf

Phyllanthus amarus has anti-inflammatory potential by inhibition of iNOS, COX-2, and cytokines via the NF-κB pathway

Extracellular heat shock protein 60 (HSP60) has been considered a proinflammatory danger signal. Yet, HSP60 can also down-regulate experimental immune arthritis and diabetes models by specific inhibition of Th1-like responses. We now report that HSP60 in vitro differentially modulates the expression of Th1/Th2 transcription factors in human T cells: HSP60 down-regulates T-bet, NF-κB, and NFATp and up-regulates GATA-3, leading to decreased secretion of TNF-α and IFN-γ and enhanced secretion of IL-10. These effects depended on TLR2 signaling and could not be attributed to LPS or to other contaminants. In BALB/c mice, HSP60 in vivo inhibited the clinical, histological, and serological manifestations of Con A-induced hepatitis associated with up-regulated T cell expression of suppressor of cytokine signaling 3 and GATA-3 and down-regulated T-bet expression. These results provide a molecular explanation for the effects of HSP60 treatment on T cell inflammation via innate regulation of the inflammatory response.

/pdf/heat-shock-protein-60-inhibits-th1-mediated-hepatitis-model-3lstwvw3m6.pdf

Heat Shock Protein 60 Inhibits Th1-Mediated Hepatitis Model via Innate Regulation of Th1/Th2 Transcription Factors and Cytokines

Involvement of IL-10, an anti-inflammatory cytokine in murine liver injury induced by Concanavalin A

Background: The disease behavior in cases of newly diagnosed IIPs has rarely been investigated prospectively. Methods: In JIPS registry, progression-free survival (PFS) and the percentage of cases meeting progressive fibrosing interstitial lung disease (PF-ILD) criteria were longitudinally investigated. PFS was defined as duration without any event of death, an absolute decline of forced vital capacity (FVC) ≥10%, onset of acute exacerbation, or a decline of &gt;50 meters in the 6-minute walk distance. The PF-ILD criteria were defined as: 1) relative annual decline of FVC ≥5%, 2) FVC decline ≥2.5% and worsening of mMRC or CT findings, or 3) worsening of mMRC and CT findings. Results: In 866 cases with IIPs, mean age was 70 years, and mean FVC %predicted was 80%. The most common was IPF (469 cases), followed by unclassifiable IIP. Median PFS of IPF and unclassifiable IIP were 24.2 and 24.6 months, respectively (HR = 0.91 (95%CI: 0.76–1.10), log-rank test: p = 0.345). Three-year progression-free rates for IIPs, IPF, and unclassifiable IIP were 40%, 36%, and 40%, respectively. After 1 and 2 years, 23% and 37% met the PF-ILD criteria for IIPs: 24% and 42% for IPF, and 23% and 39% for unclassifiable IIP. Conclusions: Among newly diagnosed IIP cases, the prognosis of unclassifiable IIP was similar to that of IPF within 3 years. (NCT03041623)&nbsp;

Nationwide prospective registry of idiopathic interstitial pneumonias with central multidisciplinary diagnosis in Japan (JIPS Registry): Analysis of disease progression

Mitsuro Kato

Papers

Involvement of IL-10, an anti-inflammatory cytokine in murine liver injury induced by Concanavalin A

Nationwide prospective registry of idiopathic interstitial pneumonias with central multidisciplinary diagnosis in Japan (JIPS Registry): Analysis of disease progression