Anti-CSF2 monoclonal antibody, clone CWE3-32D22 [APC]

Objective and design To investigate whether di-(2-ethylhexyl) phthalate (DEHP) affects the production of inflammatory cytokines by human macrophages. Materials and methods Differentiated macrophage-like THP-1 cells were exposed to 200 mu M DEHP for 3 h, followed by incubation in the presence or absence of opsonized zymosan A, and the concentrations of TNF-alpha, IL-1 beta, IL-8, and IL-6 in the culture media were determined by ELISA. DNA microarray and quantitative real-time RT-PCR analyses were performed to identify genes that showed changes in expression in response to DEHP. Results DEHP treatment increased the concentrations of TNF-alpha, IL-1 beta, IL-8, and IL-6 in the media, regardless of whether the cells phagocytosed zymosan. DNA microarray analysis showed that DEHP increased the levels of expression of IL-8, CXCL1, CXCL2, CXCL3, CXCL6, CCL3, MMP3, MMP10, MMP14, and CSF2 mRNA, and real-time RT-PCR showed that DEHP significantly enhanced the levels of expression of IL-8, CXCL1, CXCL2, CXCL3, CXCL6, CCL3, MMP10, CSF2, TNF-alpha, IL-1 beta, and IL-6 mRNA in THP-1 cells. DEHP significantly induced translocation of p65 NF-kappa B into the nucleus. Conclusion DEHP enhances the production of inflammatory cytokines and chemokines by macrophages, and exacerbates their inflammatory response.

The transcriptional activator I kappa B zeta is a key regulator of psoriasis, but which cells mediate its pathogenic effect remains unknown. Here we found that I kappa B zeta expression in keratinocytes triggers not only skin lesions but also systemic inflammation in mouse psoriasis models. Specific depletion of I kappa B zeta in keratinocytes was sufficient to suppress the induction of imiquimod- or 1L-36-mediated psoriasis. Moreover, I kappa B zeta ablation in keratinocytes prevented the onset of psoriatic lesions and systemic inflammation in keratinocyte-specific 1L-17A-transgenic mice. Mechanistically, this psoriasis protection was mediated by I kappa B zeta deficiency in keratinocytes abrogating the induction of specific proinflammatory target genes, including Excl5, Excl2, Csf2, and tsf3, in response to 1L-17A or 1L-36. These I kappa B zeta-dependent genes trigger the generation and recruitment of neutrophils and monocytes that are needed for skin inflammation. Consequently, our data uncover a surprisingly pivotal role of keratinocytes and keratinocyte-derived I kappa B zeta as key mediators of psoriasis and psoriasis-related systemic inflammation.