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Tumor necrosis factor-\u03b1 (TNF-\u03b1) has been implicated in the pathogenesis of septic kidney injury; however, the sites and mechanisms of renal TNF-\u03b1 production during sepsis remain to be defined. In the present study, we showed that TNF-\u03b1 expression is increased in medullary thick ascending limbs (MTALs) of mice with sepsis induced by cecal ligation and puncture. Treatment with lipopolysaccharide (LPS) for 3 h in vitro also increased MTAL TNF-\u03b1 production. Sepsis and LPS increased MTAL TNF-\u03b1 expression through activation of the myeloid differentiation factor 88 (MyD88)-IL-1 receptor-associated kinase 1-ERK signaling pathway. Pretreatment with monophosphoryl lipid A (MPLA), a nontoxic immunomodulator that protects against bacterial infection, eliminated the sepsis- and LPS-induced increases in MTAL TNF-\u03b1 production. The suppressive effect of MPLA on TNF-\u03b1 was mediated through activation of a phosphatidylinositol 3-kinase-dependent pathway that inhibits MyD88-dependent ERK activation. This likely involves MPLA-phosphatidylinositol 3-kinase-mediated induction of Tollip, which negatively regulates the MyD88-ERK pathway by inhibiting activation of IL-1 receptor-associated kinase 1. These regulatory mechanisms are similar to those previously shown to mediate the effect of MPLA to prevent sepsis-induced inhibition of MTAL [Formula: see text] absorption. These results identify the MTAL as a site of local TNF-\u03b1 production in the kidney during sepsis and identify molecular mechanisms that can be targeted to attenuate renal TNF-\u03b1 expression. The ability of MPLA pretreatment to suppress MyD88-dependent ERK signaling in the MTAL during sepsis has the dual beneficial effects of protecting tubule transport functions and attenuating harmful proinflammatory responses.<\/jats:p>","DOI":"10.1152\/ajprenal.00178.2020","type":"journal-article","created":{"date-parts":[[2020,5,18]],"date-time":"2020-05-18T16:46:47Z","timestamp":1589820407000},"page":"F8-F18","source":"Crossref","is-referenced-by-count":13,"title":["Monophosphoryl lipid A pretreatment suppresses sepsis- and LPS-induced proinflammatory cytokine production in the medullary thick ascending limb"],"prefix":"10.1152","volume":"319","author":[{"suffix":"3rd","given":"Bruns A.","family":"Watts","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Tamayo","sequence":"additional","affiliation":[{"name":"Department of 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