Transgenic Mice Showing Inflammation-Inducible Overexpression of Granulocyte Macrophage Colony-Stimulating Factor

Abstract

We used the promoter of the human C-reactive protein (CRP) gene to drive inflammation-inducible overexpression of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in transgenic mice. Transgenic mice carrying a CRP/GM-CSF fusion gene show a >150-fold increases in circulating levels of GM-CSF within 6 h of intraperitoneal inoculation with 25 g of lipopolysaccharide. However, some of the transgenic mice also display relatively high basal levels of GM-CSF in the absence of any obvious inflammatory stimulus. Raised basal levels of GM-CSF are associated with a number of pathological changes, including enlarged and histologically abnormal livers and spleens and with increases in the number and activation state of macrophages and granulocytes in the peripheral blood. Despite problems associated with the expression of such a potent pleiotropic cytokine as GM-CSF, the principle of inflammation-inducible expression of chimeric constructs has been shown to be feasible. Inducible expression systems such as that described here could be of potential use in the study of the role of cytokines in health and disease and in the development of disease-resistant strains of livestock.

Modulation of pulmonary DC function by vaccine‐encoded GM‐CSF enhances protective immunity against Mycobacterium tuberculosis infection

“…1), suggests that fine control of GM-CSF may be required to adequately fight chronic bacterial infections and avoid prolonged inflammation. Short-term persistence of BCG:GM-CSF in vivo may be sufficient to adequately stimulate immune function, without the immunopathology associated with sustained production of GM-CSF within the lung itself [14,15], or non-organ-specific, transgenic expression of the cytokine [27]. It is also clear that targeted delivery of GM-CSF to the lung is crucial for the protective effect of the vaccine, as we observed no improved protection in the lung when BCG was administered subcutaneously, even at 4 wk post-vaccination where BCG:GM-CSF-induced protective immunity was maximal (data not shown and Fig.…”

Hydrogel-Delivered GM-CSF Overcomes Nonresponsiveness to Hepatitis B Vaccine through the Recruitment and Activation of Dendritic Cells

“…Similar polymer-or gel-formulated GM-CSF had been used to enhance the vaccine efficacy of tumor peptides or Ags (43,44), supporting the general application of this approach to improve the immunogenicity of low-immunogenic proteins. In addition to enhancing vaccine efficacy, an advantage of local GM-CSF delivery is that it avoids potential side effects associated with systemic administration of GM-CSF, such as the induction of histologically abnormal livers and spleens accompanied by an increased number and activation state of inflammatory cells (45,46), as well as the generation of CD11b It is known that the primary protective immune response induced by rHBsAg vaccine is provided by anti-HBs Abs, and the successful production of anti-HBs Abs is critically dependent upon T cells. In the hypo-and nonresponder individuals, lack of response to HBsAg has been attributed to a number of mechanisms, including a defect in the generation of primary HBsAg-specific T cells (12)(13)(14)(15)(16) or deficient B cell repertoires (50,51).…”

Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression

“…2A). The human CRP promoter was shown to combine the advantages of low basal transgene expression with the potential of a marked increase in response to inflammatory stimuli (18). Because this promoter includes a signal peptide sequence, transgene product would be exteriorized from liver cells and reach tissue extracellular medium via the blood stream.…”