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However, it serves as a damage\u2010associated molecular pattern protein that activates immune cells and stimulates inflammatory cytokines to accentuate neuroinflammation after release from damaged cells. In contrast, Inter\u2010alpha Inhibitor Proteins (IAIPs) are proteins with immunomodulatory effects including inhibition of pro\u2010inflammatory cytokines. We have demonstrated that IAIPs exhibit neuroprotective properties in neonatal rats exposed to hypoxic\u2010ischemic (HI) brain injury. In addition, previous studies have suggested that the light chain of IAIPs, bikunin, may exert its anti\u2010inflammatory effects by inhibiting HMGB1 in a variety of different injury models in adult subjects. The objectives of the current study were to confirm whether HMGB1 is a target of IAIPs by investigating the potential binding characteristics of HMGB1 and IAIPs in vitro\n                    <jats:italic>,<\/jats:italic>\n                    and co\u2010localization in vivo in cerebral cortices after exposure to HI injury. Solid\u2010phase binding assays and surface plasmon resonance (SPR) were used to determine the physical binding characteristics between IAIPs and HMGB1. Cellular localizations of IAIPs\u2010HMGB1 in neonatal rat cortex were visualized by double labeling with anti\u2010IAIPs and anti\u2010HMGB1 antibodies. Solid\u2010phase binding and SPR demonstrated specific binding between IAIPs and HMGB1\u00a0in vitro. Cortical cytoplasmic and nuclear co\u2010localization of IAIPs and HMGB1 were detected by immunofluorescent staining in control and rats immediately and 3\u00a0hours after HI. In conclusion, HMGB1 and IAIPs exhibit direct binding in vitro and co\u2010localization in vivo in neonatal rats exposed to HI brain injury suggesting HMGB1 could be a target of IAIPs.\n                  <\/jats:p>","DOI":"10.1096\/fj.202002109rr","type":"journal-article","created":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T13:19:53Z","timestamp":1612963193000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["High\u2010mobility group box\u20101 and inter\u2010alpha inhibitor proteins: In vitro binding and co\u2010localization in cerebral cortex after hypoxic\u2010ischemic injury"],"prefix":"10.1096","volume":"35","author":[{"given":"Kazuki","family":"Hatayama","sequence":"first","affiliation":[{"name":"Women &amp; Infants Hospital of Rhode Island Alpert Medical School of Brown University Providence RI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ray H.","family":"Chen","sequence":"additional","affiliation":[{"name":"Women &amp; Infants Hospital of Rhode Island Alpert Medical School of Brown University Providence RI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan","family":"Hanson","sequence":"additional","affiliation":[{"name":"Women &amp; Infants Hospital of Rhode Island Alpert Medical School of Brown University Providence RI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyoshi","family":"Teshigawara","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Okayama University Graduate School of Medicine Okayama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Qiu","sequence":"additional","affiliation":[{"name":"ProThera Biologics, Inc. 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