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The Colts looked dangerous on the opening drive of the game as TY Hilton picked up a big gain to move the AFC South side within 20 yards of the endzone, but the drive stalled leaving the team to settle for an Adam Vinatieri field goal.
The Steelers soon edged ahead though, with Roethlisberger connecting with a wide-open Markus Wheaton for an easy touchdown for the rookie wide receiver.
Luck did manage to close the gap a few minutes later, picking out tight end Dwayne Allen with a 23-yard effort down the sideline.
Antonio Brown continued his bright start to the 2014 season, making the most of a Colts penalty during a field goal, which gave the Steelers a first down, to haul in an acrobatic touchdown catch. He added another on the next drive, sprinting most of the way after collecting the ball from Roethlisberger.
A late rally before the break from Luck and the Colts offense kept the visitors in contention at the interval, as Hilton made a quick run down the sideline for the team's second touchdown of the day, before Vinatieri kicked another field goal.
Roethlisberger and the Steelers offense continued to look threatening at the start of the third, resulting in a second touchdown for Bryant to put the AFC North team 22 points ahead.
It looked like Pittsburgh would be in again shortly after when Heath Miller picked up a big gain, but the drive stalled and the Steelers were forced to punt for the first time.
Running back Ahmad Bradshaw had been kept quiet in the first half, but ran the ball in from seven yards out in a bid to launch a comeback for the visiting side.
The Colts got the ball back almost straight away after Darrius Heyward-Bey, who spent last season with Indianapolis, fumbled the ball after taking a catch from Roethlisberger.
The turnover set the Colts up to add their second touchdown in just over a minute, with Luck spotting Donte Moncrief in space down the sideline to give the rookie his first score in the NFL.
Indianapolis's resurgence was halted though when Luck was penalised for intentional grounding in the endzone, giving the home side a safety.
Roethlisberger came back out with the Steelers offense, and completed over 500 passing yards for the first time in his NFL career on his way to finding Miller with his sixth touchdown pass of the game.
Luck thought that he could get the ball to Hilton with a long throw, but Antwon Blake stayed with the pacy receiver to get an interception, all but ending the Colts' hopes of a win.
Despite the loss, the Colts remain top in the AFC South with a 5-3 record, while the Steelers' first back-to-back wins of the season leaves them third in the AFC North, just behind the Bengals and Ravens.